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Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Cite this: J. Med. Chem. 2018, 61, 14, 5822–5880
Publication Date (Web):February 5, 2018
https://doi.org/10.1021/acs.jmedchem.7b01788
Copyright © 2018 American Chemical Society
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Abstract

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Introduction

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The design of bioisosteres is a useful principle in drug design that, although widely practiced, is contextual in application. Thus, the design of bioisosteres requires detailed insight into the physicochemical properties of an element, heterocycle, or functional group if effective emulation is to be achieved and, ideally, complemented by a similar level of understanding of the binding site of a molecule.(1) Bioisosterism has its origins in the concept of isosterism between relatively simple functionality and small molecules that was advanced by Moir and Langmuir a century ago.(1) However, contemporary interpretations of structural metaphors in a biological setting accommodate a much broader range of bioisosteric structural motifs that can vary considerably in size and shape from the functionality being emulated.(1,2) Thus, modern bioisosteric relationships are rooted far more in functional reproduction of biochemical pharmacological properties that reflect aspects of molecular recognition that are often unique to a specific environment.(1) Consequently, the relationship between shape and/or aspects of physicochemical properties of a bioisostere can be oblique. Fluorine has played a prominent role in drug design since the approval of the first fluorinated drug, the synthetic 9α-fluoro-substituted corticosteroid fludrocortisone (1), on August 18, 1955.(3) The applications of fluorine in the design of drugs and agricultural chemicals continues to grow as our knowledge and understanding of how to take full advantage of the unique properties of this element matures.(4−6) This has been fostered by the development of innovative synthetic methodology which is providing access to new fluorinated motifs with interesting topographies and physicochemical attributes.(7) While early applications of fluorine as a bioisostere focused on the relatively simple replacement of hydrogen atoms in drug molecules, often as a means of influencing metabolism, the last 20 years has seen broader deployment of fluorine and fluorinated motifs in the construction of more sophisticated structural arrangements that are able to emulate and influence a number of more traditional functionalities. In this Perspective, I provide a synopsis of some of the practical applications of fluorine as a bioisostere in drug design, ranging from the simple substitution of the hydrogen atom in the setting of alkyl and aromatic moieties to examples that utilize fluorine in conjunction with additional functionalities to explore bioisosteric relationships that are more esoteric in nature and which are, in some cases, less well developed.

Key Properties of Fluorine of Relevance to Bioisostere Design

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The effective application of fluorine in drug design requires an understanding of its key physicochemical properties, and those of relevance to the design of bioisosteres are summarized in Table 1.(4,8) Fluorine is approximately 20% larger than hydrogen based on comparison of the van der Waals radii, while the length and size of a C–F bond is more closely aligned with a C═O bond than either the shorter C–H or longer C–OH, C–C≡N, or S═O bonds. The electronegativity of fluorine is closer to that of oxygen, which is reflected in the dipole moment of the C–F bond being larger and in the opposite direction of a C–H but less than that of C═O, S═O, C–OH, and C–C≡N moieties. Fluorine is modestly more lipophilic than a hydrogen atom and significantly more lipophilic than OH, C═O, C≡N, or sulfoxide and sulfone substituents. Unlike chlorine, bromine, and iodine, fluorine does not engage in halogen bonding and is nonpolarizable, a property that underlies strong electrostatic interactions which can be attractive or repulsive.(4) These properties confer fluorine with considerable versatility such that it has been explored as a potential bioisostere of the hydrogen atom, carbonyl and sulfonyl functionalities, the carbinol moiety, and the nitrile, with effective functional mimicry very much dependent upon the biochemical context.
Table 1. Key Properties of the C–F Bond Compared to the C–H, C═O, C–OH, C–C≡N, and S═O Bonds
bondbond length (Å)van der Waals radius (Å)van der Waals volume of atom (Å3)total size (Å3)electronegativity of the elementdipole moment μ (D)πbond dissociation energy (kcal/mol)
C–H1.091.207.242.292.20∼−0.4098.8
C–F1.351.4713.312.823.981.410.14105.4
C–Cl1.771.7522.45 3.161.87 (CH3Cl)0.7178.5
C═O1.231.5214.712.733.442.33 (H2C═O)CHO: −0.6585 (π bond)
C–OH1.43 (CH3OH)1.5214.71 3.442.87 (CH3OH)–0.6784.0
 1.48 (CH3 CH2OH)    1.66 (CH3 CH2OH)  
C–C≡N2.22 (HCN)    3.92 (CH3CN)–0.57 
S═O1.44 (CH3SO2 CH3)1.5214.71 3.444.44 (CH3SO2 CH3)(9)CH3SO: −1.58 
       CH3SO2: −1.63 

Fluorine as a Bioisostere of the Hydrogen Atom in Alkyl Moieties

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Developability Aspects Associated with Fluorination and the Size of the CF3 Moiety

Replacing hydrogen atoms with fluorine has been explored extensively in drug design, most commonly to replace those bound to an aromatic ring or in the context of a CF3 for CH3 replacement where these substitutions can modulate potency or interfere with metabolic modification.(10) The replacement of a hydrogen atom by fluorine would be expected to add to the physical size, modestly increase the lipophilicity of a molecule based on the π coefficient of 0.14 determined for fluorine, but more significantly increase molecular weight (MW) (Table 1). Thus, the replacement of a CH3 by CF3 would be expected to increase the overall lipophilicity of a molecule (cLog P) by 0.42 and add 54 Da to the MW, parameters that would be anticipated to negatively affect ligand efficiency metrics.(11) However, fluorination of a molecule does not necessarily lead to an increase in lipophilicity, and several structural motifs are associated with increased polarity based on a matched molecular pairs (MMP) analyses.(4d,12) Fluorine atoms that are deployed in a molecule such that they are proximal to an oxygen atom, separated by a distance of <3.1 Å, can exhibit a lower measured Log P value, while vicinal alkyl fluorides offer increased polarity as a function of C–F dipole alignment that is favored by the gauche effect, stabilizing a more polar conformation (vide infra). Adding to these observations, concerns around the effect of fluorination on ligand efficiency metrics has been addressed by a careful MMP analysis of the performance of a large data set of compounds evaluated in in vitro developability assays.(13) This study, in which fluorine was present in a range of environments but most commonly incorporated as an aryl-F, aryl-CF3, or an aryl-CF2H motif, concluded that polyfluorination may not necessarily represent a deleterious modification. On the basis of an analysis of P-glycoprotein (P-gp) recognition, lipophilicity, metabolic stability, and membrane permeability using assays conducted in vitro, fluorine was found to behave more like a hydrogen atom, leading to the contention that up to five fluorine atoms can be introduced into a molecule without a significant impact on performance in these assays.(13) As a consequence, it was suggested that the MW increase associated with the introduction of fluorine may be ignored in efficiency metric calculations and that the fluorine-corrected molecular weight MWFC (MWFC = total MW – MW of the fluorine atoms present in the molecule) should be used as a more suitable and relevant descriptor for this purpose.(13)
The size of the CF3 moiety has also been somewhat challenging to definitively assess and this moiety has often been considered to be isosteric with an iso-propyl substituent, although it is clearly of a different shape.(4g) The calculated van der Waals volumes, the A values, and both experimental measures of biphenyl rotational interference compiled in Table 2 all indicate that the CF3 is a smaller than an iso-propyl substituent with the exception of the Taft Es value which uniquely indicates the reverse, although the differences projected by several of these measurements are relatively modest.(14,15) Under some circumstances, the CF3 moiety has been found to sterically dominate a phenyl or tert-butyl substituent in defining the stereochemical outcome of an aldol reaction.(15d−f) Assessing the size of the CF3 moiety in biochemical applications is unlikely to simplify the inherent complexity associated with this question given the context-dependent nature of drug–target interactions. Nevertheless, an experiment designed to compare the size of the CF3 and an iso-propyl substituent in a biological context has been conducted with matrix metalloprotease-9 inhibitors where the alkyl side chains of 2 and 3 project into the well-defined lipophilic S1′ pocket of the enzyme.(16) In both series, an alkyl chain terminating in CH3 or CH3CH2 was associated with potent inhibitory activity, while the respective iso-propyl homologues were over 1000-fold weaker; however, the two CF3-substituted derivatives largely retained the potency of the smaller alkyl groups, data captured in Table 2. These results indicate that, in this specific context, the CF3 moiety could be considered to be bioisosteric with an ethyl rather than an iso-propyl substituent.(16)
Table 2. Comparisons of the Size of Alkyl and CF3 Groups Based on Van Der Waals Volume, A Values, Taft Es Values, Biphenyl Interference Values, and the Activity of the Two Structurally-Related Series of MMP-9 Inhibitor Probes 2 and 3
 vdW volume (Å3)A value (kcal/mol)Taft Es valuebiphenyl rotational interference value (kcal/mol)(14)experimental biphenyl rotational B value (ΔGrot, kcal/mol)(15)inhibition of MMP-9 by 2/3 IC50 (nM)(16)
H1.20 0   
F13.30.15–0.464.64.4 
Me21.61.70–1.249.77.41/10
Et38.91.70–1.31 8.72/27
CF339.82.10–2.4012.110.587/22
iPr56.22.15–1.7112.611.11800/4500
tBu >4.50–2.7818.315.4 

Fluorination as an Approach to Reducing Metabolism

Because the introduction of fluorine can lead to resistance toward oxidative metabolism, fluorination has developed into a popular approach to addressing the poor pharmacokinetic performance of compounds in vitro and in vivo.(10,17) Under some circumstances, a CH3 substituent can be replaced directly by a fluorine atom despite being 40–50% smaller, although metabolically labile alkyl groups are more commonly addressed by more sophisticated motifs in which the CF3 moiety plays a prominent role. While the introduction of fluorine is often directed specifically toward a metabolic soft spot, the effects of fluorination can be indirect and complex. As a consequence, the effect can range from negative or null, possibly due to redirecting metabolism to an alternative site, to global protection toward metabolic modification, while the effects exerted on the metabolic stability of proximal functionality can be positive or negative dependent upon context.(18−20)
Examples where replacing hydrogen atoms with fluorine exerts a positive effect on metabolism are provided by the taxoids 4 and 5, which are related to paclitaxel (6) and the GPR119 agonists 7 and 8.(21,22) For the taxoid derivatives, CYP 3A4 oxidation of the C-3′ iso-butenyl CH3 groups of 4 represented an important metabolic pathway that prompted replacement of the allylic methyl substituents by fluorine, affording 5. Fluorinated derivative 5 exhibited highly potent cytotoxicity toward a series of human cancer cell lines, with a 10–1000-fold advantage over 6.(21) Remarkably, 5 was quite resistant to metabolic modification in the presence of CYP 450 enzymes, with the introduction of the two fluorine atoms providing protection against metabolic modification at the C-3′ N-t-Boc and C-6 methylene moieties known to be the major sites of metabolic lability in the homologue 6.(21)
In the example provided by GPR119 agonists, compound 7 displayed poor metabolic stability in vitro which was attributed to its high lipophilicity, ELog D = 4.3.(22) Replacing of the CH3 substituent β- to the amide N atom with fluorine afforded 8, which exhibited enhanced metabolic stability while also illuminating aspects of the bound conformation. This was the result of the N-β-fluoroethylamide adopting a preferred conformation in which the two elements were in a gauche relationship (vide infra), which constituted about 75% of the conformer population on the NMR time scale.(22)
In a study seeking replacements for a tert-butyl moiety that would offer improved metabolic stability, systematic modifications to the 3 methyl groups were explored in the context of the simple biphenyl derivative 6-(4-(tert-butyl)phenyl)nicotinonitrile (9) (Table 3).(23,24) The effects of structural modification were compared with compound persistence when incubated in rat and human liver microsomes (RLM and HLM), respectively, with the results summarized in Table 3. While some success was achieved with the polar substituents found in 1013, these were viewed as potential liabilities in the context of a drug target where the tert-butyl group may be accommodated in a hydrophobic binding pocket. The CF3-susbstitued cyclopropyl (Cp-CF3) moiety exemplified in 17 emerged as the optimal lipophilic substituent, with higher metabolic stability in both RLM and HLM preparations than 1416.
Table 3. RLM and HLM Half-Life Values Associated with a Series of 6-(4-Substituted-phenyl) Nicotinonitrile Derivatives 917
To further demonstrate the utility of the Cp-CF3 substituent, comparison of liver microsomal stability data for six matched pairs of biphenyl amide derivatives was probed, where the outcome was a positive result in each case, and as a replacement for the metabolically labile tert-butyl moiety in the steroid 5α-reductase inhibitor finasteride (18).(24) The Cp-CF3 analogue 19 exhibited a t1/2 in HLM of 114 min which compared to 63 min for 18, with recognition that in this particular example, the modification may not protect against metabolism at other sites of the molecule and may cause a redirection of metabolism to alternative sites.
The Cp-CF3 moiety featured prominently in a complementary study in which a series of tert-butyl isosteres were the subject of detailed in vitro profiling when installed in the background of the dual endothelin A and B antagonist bosentan (20) and the CCR-9 antagonist vercirnon (21), both of which contain a 4-(tert-butyl)benzenesulfonamide moiety.(25) In this analysis, the profiles of the tert-butyl progenitors were compared with the Cp-CF3, CF3, SF5, and [1.1.1]-bicyclopentane (BCP) homologues, with the calculated relative sizes of these substituents compiled in Table 4. With the exception of Cp-CF3, all of the substituents are smaller than a tert-butyl, and Log D measurements indicated that lipophilicity increased in the order of CF3 < SF5 < Cp-CF3 < tBu < BCP while the pKa of the sulfonamide N–H increased in the order of SF5 < CF3 < Cp-CF3 < tBu ≈ BCP.
Table 4. Calculated Volumes of a Series of Substituents Normalized to the tert-Butyl Moiety
In the context of 20, the Cp-CF3- and BCP-substituted analogues performed similarly to the parent molecule as antagonists at the endothelin A and B receptors, while the CF3- and SF5-substituted derivatives were 10-fold less potent.(25) When incorporated as tert-butyl replacements in 21, all of the substituents performed similarly to the prototype in a CCR9 functional assay. In both series of compounds, there was a trend toward enhanced metabolic stability in liver microsomes for these substituents compared to the tert-butyl-substituted prototypes, with CF3 and SF5 the most effective. No significant CYP inhibitory effects were observed with either series, but the effects on solubility were varied in analogues of 20 while all of the modifications led to reduced solubility in the context of 21.
These general observations have support from examples harvested from studies conducted across a range of compound structures with widely varying biochemical mechanisms, although there are unique contextual variations in individual performance. For example, the FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (22), which is in phase 3 clinical trials for the treatment of acute myeloid leukemia (AML), is metabolized at the tert-butyl moiety in humans to afford alcohol 23.(26,27) This lability was addressed in a related series of compounds by replacing the tert-butyl substituent with Cp-CF3, with 24 characterized as a potent FLT3 inhibitor, Kd = 0.6 nM, with improved metabolic stability compared to its tert-butyl progenitor.(28)
The Cp-CF3 moiety in the human bombesin receptor subtype-3 (hBRS-3) agonist 26 provided a partial solution to the high metabolic turnover rate observed with the prototype 25, with further refinement of the carbinol CH3 to a CF3 affording the more advanced compound MK-5046 (27).(29)
The 1,1,1-trifluoro-2-methylpropan-2-yl moiety addressed the metabolic lability of the tert-butyl substituent of the selective phosphatidylinositol-3 kinase-α (PI3Kα) inhibitor 28, a precursor to alpelisib (NVP-BYL719, 29) which is currently in phase 3 clinical trials for the treatment of breast cancer (Table 5).(30) The main metabolic pathways for 28 were determined to be hydroxylation of one of the CH3 moieties of the tert-butyl element and hydrolysis of the primary amide. The design of 29 was inspired by an examination of an X-ray cocrystal structure which indicated scope to slightly enlarge the size of tert-butyl moiety in order to more completely fill the pocket of the enzyme into which it projected. In the event, the CF3 analogue not only retarded metabolism at this site, leading to lower clearance in vivo and excellent oral bioavailability (F = 106% in mouse, F = 58% in rat, and F = 140% in dog) but also enhanced potency by 2-fold. In the cocrystal structure of 28 with PI3Kα, one fluorine atom of the CF3 moiety was described as engaging in a hydrogen-bonding interaction with the protonated amine of Lys802, while the bound conformation of the inhibitor was stabilized by an intramolecular interaction between one of the lone pairs of electrons on the urea oxygen atom and the low lying C–S σ* of the sulfur atom of the thiazole, interactions depicted in Figure 1.(30,31)
Table 5. SARs, Metabolic Stability, and in Vivo Clearance Associated with the PI3Kα Inhibitors 28 and 29
 RP110α IC50 (nM)P110β IC50 (nM)P110δ IC50 (nM)P110γ IC50 (nM)RLM clearance (μL/min/mg)rat clearance in vivo (mL/min/kg)
28CH31444003304307739
29CF3512002902502910

Figure 1

Figure 1. Key drug–target interactions between 29 and the PI3Kα enzyme and conformational bias provided by an intramolecular O to S interaction.

Similarly, in a series of inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) that led to the discovery of CEP-32496 (30), the 1,1,1-trifluoro-2-methylpropan-2-yl substituent was a more effective bioisostere of a tert-butyl substituent that adequately addressed the metabolic lability associated with the prototype, preserving potency in this example more effectively than a Cp-CF3 substituent which was a 2-fold weaker enzyme inhibitor.(32)
In a series of γ-secretase modulators based on the tert-butyl-substituted lead compound 31, which combined modest potency with poor metabolic stability, substituting one of the CH3 moieties with a CF3 gave 32, which significantly improved both parameters (Table 6).(33) This result allowed further refinement of the structure by pruning of the substituent which revealed that both potency and metabolic stability were dependent upon the absolute configuration of the trifluoroethyl moiety. The (R)-isomer 33 was found to be superior to the (S)-antipode 34 and it was this motif that was retained in the optimized molecule 35 where the addition of a CH3 moiety to the linker element was found to improve potency by a further 3-fold. More recently the CF3 oxetane was evaluated as a tert-butyl replacement in the context of 36, a modification that retained biological potency while lowering E Log P, enhancing LipE, and improving metabolic stability in HLM compared to 31.(34)
Table 6. SARs, Lipophilicity, and Metabolic Stability Associated with a Series of γ-Secretase Modulators 3136a
a

*LipE = pIC50 – Log P.

The triazole-based CF3 substituent in sitagliptin (40), a potent dipeptidyl peptidase-4 (DPP-4) inhibitor marketed for the treatment of type 2 diabetes, is an important determinant of both its in vitro and in vivo profile.(35) In this example, the CF2H (38) and CF3 (40) moieties performed more effectively as bioisosteres of the CH3 in prototype 37, while the CF2CF3 substituent in 39 resulted in 2-fold lower enzyme inhibitory potency (Table 7). Strikingly, while the oral bioavailability of each of the 3 fluorinated 3840 derivatives in the rat was significantly improved compared to 37, this was not the result of significant changes in clearance in vivo.
Table 7. SAR, Metabolic Stability, and Oral Bioavailability of the Series of DPP-4 Inhibitors 3740
 RDPP-4 IC50 (nM)rat clearance (mL/min/kg)oral bioavailability (F, %)a
37CH2CH337702
38CF2H296639
39CF2CF3715861
40CF3186076
a

Dose = 1 mg/kg IV; 2 mg/kg PO.

Fluorination of the terminal CH3 groups of the γ-secretase inhibitor 41 was examined as an approach to address the metabolic modification that had been determined to occur at this site.(36) By replacing the CH3 groups with CF3, intrinsic enzyme inhibitory activity was improved marginally from an IC50 value of 25 nM for 41 to 16 nM for begacestat (42), while the t1/2 in RLM increased from 1 to 8 min. This effect extended to mouse LM, where the t1/2 increased from 2 to 24 min, but not to HLM, where the measured t1/2 values for 41 and 42 were comparable at 8 min. The improved metabolic stability in mouse LM translated to enhanced exposure and better efficacy at lowering Aβ42 levels in mice in vivo, leading to 42 being selected for clinical evaluation.
Fluorination of amide-bound alkyl groups has been shown to interfere with oxidative N-dealkylation processes.(37,38) For example, replacing the iso-butyl amide substituent of the tetrahydroisoquinolone-based antimalarial agent 43 with the trifluoroethyl moiety found in 44 resulted in only a modest reduction in cell-based potency while metabolic stability in mouse LM was substantially increased.(37) Similarly, the CF3CH2 substituent in the slowly activating cardiac delayed rectifier potassium current (IKs) inhibitor 46 (L-768,673) was designed to interfere with the N-dealkylation observed with the N-methyl analogue 45, a known metabolic pathway for benzodiazepine derivatives, and this compound exhibited long lasting effects on the QT interval in dogs in vivo.(38)
The heptafluoroisopropyl substituent was originally explored in the agricultural chemistry arena and is found in the pesticides flubendiamide (47), which activates insect ryanodine (Ry)-sensitive intracellular Ca2+ release channels, and broflanilide (48), a noncompetitive insect γ-aminobutyric acid (GABA) receptor antagonist.(39) This moiety has also found application in drug design campaigns where it has been evaluated as a substitute for the iso-propyl and tert-butyl substituents, most notably in the context of the hypocholesterolemic steroid 50 and the bosentan analogue 51, both of which offer improved metabolic stability compared to their progenitors 49 and 20, respectively.(40,41) While 50 demonstrated higher potency toward lowering serum cholesterol levels in rats in vivo following oral dosing, 51 bound to the ETA receptor with 16-fold reduced affinity (IC50 = 75.4 nM) compared to 20 (IC50 = 4.7 nM) although the selectively index over the ETA receptor was enhanced.
The selective aspartate semialdehyde dehydrogenase inhibitor 53 offers enzyme inhibitory potency comparable to the tert-butyl derivative 52, while substitution of the iso-propyl moiety in the hypoglycemic agent 54 with either tert-butyl (54) or heptafluoroisopropyl (56) led to reduced effects on sugar levels in vivo.(42,43)
In a series of inhibitors of aryl urea-based soluble epoxide hydrolase (SEH) inhibitors, fluorination of the phenyl substituent group conferred increased potency with the CF3 (59) and CF3O (60) analogues 3- and 6-fold more potent than the iso-propyl (57) and tert-butyl (58) prototypes, respectively (Table 8).(44) However, the heptafluorisopropyl substituent in 61 provided a uniquely potent inhibitor, with an almost 20-fold advantage over 59 and 60. Interestingly, while the aqueous solubility of 61 was 15-fold lower than 59, the CF3O-substituted derivative 60 was 8-fold more soluble than both 57 and 59, an observation not anticipated by the predicted lipophilicity values.
Table 8. Structure and Inhibitory Potency of a Series of Soluble Epoxide Hydrolase (SEH) Inhibitors
 RSEH IC50 (nM)solubility (μg/mL)
57iPr1.172.60
58tBu2.440.02
59CF30.372.60
60CF3O0.3622.5
61(CF3)2CF0.020.17
One word of caution with respect to the taking advantage of the heptafluoroisopropyl moiety as an aromatic substituent is the potential for it to exist as atropisomers when there is a large ortho- substituent. This has been observed with 62, where the 1H NMR spectrum indicated a 60:40 ratio of rotamers, with 62a identified as the major component (Figure 2).(45) The coalescence temperature, as determined from monitoring the C-6 proton in Cl2DCCDCl2, was 108 °C, corresponding to an energy barrier of 19.4 kcal/mol. A similar observation was made with the naphthalene and benzofuran analogues in which the pyrazole ring of 62 is replaced by benzene and furan, respectively.

Figure 2

Figure 2. Atropoisomerism associated with 4-(perfluoropropan-2-yl)-1H-indazol-5-amine.

The strategic deployment of a fluorine atom can exert an effect on drug metabolism and toxicity in a less direct fashion, as exemplified by the design of the fluoro analogue 64 of the anticonvulsant felbamate (63).(46) Clinical use of 63 is associated with aplastic anemia and hepatotoxicity that is idiosyncratic in frequency and which has been suggested to be due to metabolic release of atropaldehyde (66), a bivalent electrophile capable of cross-linking proteins.(46,47) The mechanism of release of 66 is postulated to occur by the metabolic process depicted in Scheme 1 and is believed to be the consequence of an irreversible retro-Michael reaction that results in the elimination of H2O and CO2 from 65. The formation of 66 is efficiently blocked by the fluorine atom present in 64, which prevents the fluorinated metabolite analogous 65 from undergoing the retro-Michael reaction.(47) The preclinical anticonvulsant profile of 64 compares favorably to 63 and is, in some circumstances, superior, and this compound has been advanced into clinical trials.(48,49)

Scheme 1

Scheme 1. Metabolism of 63 and the Release of 66

Metabolic Activation of Fluoro-alkyl Derivatives

Despite the high strength of the C–F bond (Table 1) and the relatively poor ability of fluoride to act as a leaving group, circumstances have been documented where an alkyl fluoride derivative undergoes metabolic activation that sets the stage for the elimination of HF from sp3-hybridized carbon centers.(8,50) Fluorine atoms are introduced into the ring of pyrrolidine derivatives as an isostere of hydrogen designed to interfere with metabolism, moderate the basicity of the nitrogen atom if so configured, or modulate ring conformation (vide infra). However, one circumstance where this structural configuration presented problems is exemplified by the DPP-IV inhibitor 67, which was observed to generate protein adducts when incubated in RLMs.(50) The protein covalent binding associated with 67 was irreversible and dependent on both time and NADPH but could be abrogated by including GSH or N-acetyl cysteine in the incubation medium. Trapping experiments using semicarbazide, a hard nucleophile that reacts with aldehydes, helped to elucidate the metabolic pathway depicted in Scheme 2. Metabolic activation is believed to be initiated by α-hydroxylation adjacent to the nitrogen atom of the pyrrolidine ring to give the hemiaminal 68 that, upon ring opening to the aldehyde 69, is configured for the elimination of HF to form the Michael acceptor 70. The unsaturated aldehyde 70 is an electrophile with dual sites of reactivity and thus has the potential to cause protein cross-linking. However, the addition of a soft nucleophile like GSH would provide 71, which is presumably in equilibrium with the ring closed form 72.

Scheme 2

Scheme 2. Metabolic Activation Pathway Deduced for the DPP-4 Inhibitor 67
Although this example provides a cautionary note with respect to the bioisosteric replacement of hydrogen by fluorine in pyrrolidine and, presumably, the homologous piperidine rings, detailed studies with the difluorinated pyrrolidine-based DPP-IV inhibitors 73 and 74 have indicated that for these molecules, this specific metabolic pathway is not followed.(51) The HIV-1 non-nucleoside reverse transcriptase inhibitor 75 exhibits a short life in RLM and HLM, and while the difluoro-pyrrolidine ring was determined to be the site of metabolism by an undetermined pathway, there was no apparent indication of reactive metabolite formation.(52)

2,2-Difluoro-1,3-benzodioxole Derivatives

The 1,3-benzodioxole moiety is a structural element in prevalent natural products found, for example, in the papaverine alkaloids, camptothecins, and several constituents of kava-kava.(53) However, this functionality is susceptible to metabolism by CYP 450 enzymes following a pathway that leads to the formation of a carbene intermediate that binds tightly to the Fe atom of the enzyme (Scheme 3). This carbene-bound intermediate is referred to as a metabolite intermediate (MI) complex that inactivates the enzyme until the complex degrades, which relieves the inhibition, with the methylenedioxy carbon atom released as carbon monoxide.(54,55) However, this step generates a catechol that can be subject to bioactivation by oxidizing enzymes, including CYP 450s, to afford ortho-quinone derivatives that are highly reactive toward both soft and hard nucleophiles.(55,56) Consequently, the benzo[d][1,3]dioxole element is considered to be a structural alert because it can be associated with drug–drug interactions, metabolic activation, and toxicities that includes hepatotoxicity.(55) For example, despite its relatively low clinical dose of 10–50 mg, the antidepressant paroxetine (76) is metabolized by CYP 2D6 in a fashion that leads to inhibition of the enzyme, inhibiting both its own metabolism and that of other drugs that are cleared by CYP 2D6.(57)

Scheme 3

Scheme 3. Cytochrome P450-Mediated Metabolism of the 1,3-Benzodioxole Moiety to a MI Complex
An appreciation of these problems has prompted the design of 1,3-benzodioxole replacements that would abrogate this metabolic pathway while preserving the physicochemical properties requisite for biological activity.(58) Deuteration of the methylene moiety represents the most conservative isosteric substitution that can slow this metabolic process while preserving biological activity and has been successful in the context of CPT-347 (77), a deuterated derivative of 76.(59) However, fluorination offers a more definitive solution, although the effects on biological potency are less predictable with increases, decreases and minimal changes described that show dependence on the specific target or chemotype within a target.(4,60−66) The fluorinated camptothecin analogue 78 was specifically designed to increase metabolic stability over the hydrogen-substituted prototype, a structural modification that resulted in improved exposure following oral administration of the compound as its prodrug 79.(60) Lumacaftor (VX-809, 80), which improves trafficking of the cystic fibrosis transmembrane regulator (CFTR) ΔF508 mutant and has been approved by the FDA for the treatment of cystic fibrosis, is a CYP inducer rather than an inhibitor and subject to limited metabolism, which involves oxidation and glucuronidation.(65) JNJ-42165279 (81) is a clinically evaluated, mechanism-based inhibitor of fatty acid amide hydrolase (FAAH) for which the 2,2-difluorobenzo[d][1,3]dioxole heterocycle was observed to be metabolically stable.(66)

Fluorination of Alkyl Groups and Conformational Effects

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In this section, the effects of fluorinating alkyl moieties proximal to a range of functional groups that can lead to an influence on the conformation of a molecule are discussed.

Fluorine for Hydrogen in Alkyl Groups Proximal to Amines

The substitution of hydrogen attached to sp3 carbon atoms by fluorine can influence the properties of a molecule significantly in a fashion that is dependent upon the nature of proximal functionality. The gauche effect between fluorine and substituents on the adjacent carbon atom can be an effective approach to influencing the conformation of a molecule.(67) The calculated energetic preferences for the gauche conformation of a series of 2-substituted, 1-fluoroethane derivatives are compiled in Table 9, and this phenomenon has been taken advantage of to probe aspects of molecular recognition.(67) Thus, the conformations of 3-F GABA 83 and 84,(68) the 2,3-difluoro GABA analogues 8588,(69) and 3-fluoro-N-methyl-d-aspartate (NMDA) derivatives 91 and 92(70) have been analyzed in order to illuminate aspects of the bound conformation of their progenitors 82 and 89, respectively, while the conformation of the GABA element in the macrocyclic heptapeptide unguisin A (93), which is isolated from the marine fungus Emericella unguis, has been probed by incorporating 8588.(71) The design principle behind these studies relies upon a gauche interaction between fluorine and the ammonium moiety to favor a specific conformation that is used to probe cognate receptors and, in the case of GABA, recognition by the transaminase. For 2,3-difluoro GABA, a gauche interaction between the two fluorine atoms provides an additional element of stereocontrol in addition to the gauche preference of the fluorine/ammonium elements.
Table 9. Calculated Stabilization Energies Favoring a Gauche Relationship in 2-Substituted 1-Fluoroethane
 stabilization energy (kcal/mol)
F0.5–1.0
OH1.0–2.0
OAc1.6
NHAc1.8
NH20.9–1.0
NH3+5.8
Fluorine was introduced at the 3-postion of GABA (82) and the individual enantiomers (R)-3-F-GABA (83) and (S)-3-F-GABA (83) evaluated as ligands for the GABAA and GABAC receptors.(68) Because the cloned GABAA receptor failed to distinguish between 83 and 84, the extended conformation A depicted in Figure 3, in which the two key functionalities are in an antiperiplanar arrangement that is available to both enantiomers, was considered to represent the bound topology. However, both the GABAC receptor and the transaminase favored 83, suggesting that conformer B depicted in Figure 3 is that recognized by these proteins because that topographical arrangement is a conformation disfavored by 84.(68) Evaluation of the difluoro homologues 8588 revealed that 85 was a more potent ligand for the GABAC receptor than either GABAA or GABAB, while 86 exhibited dual GABAA/GABAC binding.(69) Interestingly, while both 85 and 86 adopted an extended, zigzag conformation, they elicited very different effects at the GABAC receptor, with 85 an agonist while 86 acted as an antagonist.

Figure 3

Figure 3. Preferred conformation of 82 at the GABAA receptor (A) and the GABAC receptor and the transaminase enzyme (B) deduced from an evaluation of 83 and 84.

The preferred conformations of 91 and 92, fluoro-substituted derivatives of NMDA (89) which acts as an agonist at a subset of receptors that recognize glutamic acid (90), were analyzed by 1H- and 19F-NMR, which revealed that 91 adopted the conformation depicted in Figure 4.(70) However, the precise conformation of 92 could not be determined, although one conformation was ruled out and density functional theory (DFT) calculations suggested that of the other two conformations, the one reflecting the arrangement depicted in Figure 4 was not favored. The (2S,3S)-isomer 91 evoked currents at GluN2A and GluN2B receptors expressed in Xenopus laevis oocytes that were indicative of agonistic activity, while 92 was silent. As consequence, it was suggested that the active conformation is as depicted in Figure 4, a conclusion consistent with the conformation of 89 at the closely related GluN2D receptor in the cocrystal structure.(70)

Figure 4

Figure 4. Proposed active conformation of NMDA at the GluN2A and GluN2B receptors after analysis of 91 and 92.

Fluorine for Hydrogen in Alkyl Groups Proximal to Amides

The replacement of a hydrogen on a carbon atom β- to an amide nitrogen with fluorine can affect biological activity in a positive or negative fashion, a function of modulating conformational preferences due to the influence of a gauche effect between these substituents.(67) This is elegantly exemplified in the context of proline-containing ligands where fluorine is introduced at the C-4 position of the ring. N-Acetyl proline methyl ester (94) exhibits a preference for the Cγ-endo conformation (Figure 5A) that is reinforced by the introduction of a 4-(S)-fluoro substituent in 95 (Figure 5B), while the 4-(R)-fluoro derivative 96 favors the Cγ-exo conformer presented in Figure 5C.(72) The trans-(Z) topology of the amide moieties in 9496 is also favored, attributed to a stabilizing interaction between the oxygen of the tertiary amide and the exocyclic C═O carbon atom. This phenomenon is viewed as the donation of electron density from the nonbonded electrons of the amide C═O to the π* orbital of the adjacent CO2Me (or CO·NHR) substituent, which confers a detectable element of pyramidalization to the electron accepting C═O moiety (Figure 6).(73)

Figure 5

Figure 5. Conformational preferences of N-acetyl-proline methyl ester (94) (A), N-acetyl-4-(R)-fluoro-l-proline methyl ester (95) (B), and N-acetyl-4-(S)-fluoro-l-proline methyl ester (96) (C).

Figure 6

Figure 6. Acetamide conformation of 94 depicting an n → π* interaction.

The effect of C-4 fluorination of a pyrrolidine ring on biological activity has been illustrated in the context of both DPP-4 and fibroblast activation protein (FAP) inhibitors where in each case the proline moiety is installed at P1 and the nitrile engages with the active site serine of the protease in a Pinner-type reaction to reversibly form a stable iminoether.(74,75) In the series of DPP-4 inhibitors 97100, the cis-4-F-(S)-isomer 98 was 450-fold more potent than the trans-4-F-(R)-isomer 99, SAR points that cannot be attributed to a steric effect because the 4,4-difluoro homologue 100 fully retained the potent enzyme inhibitory activity of the prototype 97 (Table 10). The cis-(S)-4-fluoro substituent stabilizes the Cγ-endo pucker, while the trans-(R)-4-fluoro isomer stabilizes the Cγ-exo pucker (Figure 5), and it is this phenomenon that is believed to underlie the observed SARs. These observations were reproduced in the FAP inhibitors 102104, where the effects of fluorination and the preferred absolute configuration are identical to those observed with 97 and 98 (Table 10).(75)
Table 10. SARs for the 4-Substituted Pyrrolidine-2-nitrile-Based Inhibitors of DPP-4 (97100) and FAP (101104)
However, the SARs for fluorination of a proline moiety installed at P2 of the series of thrombin inhibitors 105108 reflected the opposite preference to that observed with the P1 moiety of DPP-4 and FAP inhibitors.(76) In this series, the trans-4-(R)-fluoro isomer 106 was 300-fold more potent than the cis-4-(S)-fluoro isomer 107, while the 4,4-dilfuoro analogue 108 was 6-fold less potent than the hydrogen prototype 105 (Table 11).
Table 11. SARs Associated with 4-Fluorination of the Inhibitors of Thrombin 105108
 RR′thrombin Ki (nM)
105HH0.6
106FH0.37
107HF110
108FF3.6
The effects of fluorination of a proline ring do not always manifest as an influence on potency. In the series of VLA-4 antagonists 109113, all three fluorinated compounds 111112 exhibited potency comparable to the parent 109 and the 4-(R)-hydroxy derivative 110, indicative of considerable tolerance for substitution at this region of the pharmacophore.(77)

Fluorine for Hydrogen in Alkyl Groups Proximal to Fluorine

An understanding of the conformational preferences of alkanes in which hydrogen atoms have selectively been replaced by fluorine can confer advantageous effects that may be useful in drug design (Figure 7).(78−81) The C–C–C bond angle of the R–CF2–R moiety widens to ∼118°, while the F–C–F angle is narrowed to ∼104° relative to normal tetrahedral carbon bond angles, which can manifest as a Thorpe–Ingold effect (Figure 7A).(78) When CF2 moieties are introduced in a 1,4 relationship to an alkyl chain, dipole–dipole interactions and the relief of steric buttressing favors an extended conformation (Figure 7B). Vicinal difluoroalkanes adopt a gauche conformation that overrides the unfavorable C–F dipole–dipole alignment and, as a consequence, confers increased polarity to a molecule.(79,80) For 1,3-difluoroalkanes, the conformational preferences are dictated by favorable dipole–dipole alignment, with the preferred conformation depicted in Figure 7D estimated to be 3.3 kcal/mol lower in energy than that in which the C–F dipoles project in the same direction.

Figure 7

Figure 7. Geometry of 1,1-difluoroalkanes (A), the 1,4-di-CF2 motif (B), and conformational preferences for 1,2-difluoro- (C) and 1,3-difluoro-alkanes (D).

The conformational effects of fluorination patterning have been examined in the stearic acid derivatives 114 and 115 and the substituted palmitic acids 116118.(78) The higher melting point of the (±)-threo-isomer 115 (86–88 °C) compared to the (±)-erythro-configured 114 (67–69 °C) was attributed to the ability of 115 to adopt an elongated form stabilized by F–F gauche interactions that project the alkyl moieties in an antiperiplanar arrangement, thereby minimizing unfavorable steric interactions and facilitating improved crystal packing.(78b) In contrast, the two conformations of the (±)-erythro-isomer 114 that are stabilized by F–F gauche interactions also place the alkyl chains in a gauche relationship, while the conformation with the alkyl chains antiperiplanar sacrifices the F–F gauche effects. The melting point of 118 (89.9 °C) was higher than palmitic acid (62.5 °C) and 116 (62.9 °C), while 117 was isolated as an amorphous solid that could not be obtained in crystalline form.(78a) Single crystal X-ray structures of 116 and 118 revealed extended, zigzag-type conformations that presumably facilitate crystal packing, while the amorphous nature of 117 was attributed to repulsive intramolecular effects associated with the pattern of fluorination that lead to disorder.
An example of the application of fluorination patterning to conformational control is provided by a detailed analysis of the solid state and solution conformations of a series of trifluorinated 1,3-diphenylpropane derivatives.(80) Uniquely, the all-anti isomer 119 was found to adopt a conformation that placed the two aryl rings in a topography that mimicked those of the preferred conformation calculated for 2-benzyl-2,3-dihydrobenzofuran (120). This provides an interesting example of how isosterism at the level of atom replacements (F for H) can translate into potential higher order bioisosteric relationships.
The effects of the fluorination pattern of alkyl side chains on the physicochemical properties of a molecule has been evaluated in the structurally homologous 3-propyl-1H-indoles 121126 and 3-butyl-1H-indole derivatives 127129 compiled in Table 12.(81) The experimental results revealed interesting effects of the pattern of fluorine substitution in the propyl series 121126, with the vicinal difluoro derivative 125 less lipophilic than its geminal difluoro isomer 123, reflected in the lower measured value of Log P. These properties translated into a more than 8-fold increase in aqueous solubility compared to the parent alkane 121 despite the addition of the two slightly more lipophilic fluorine atoms (Table 12). This result was attributed to the gauche interaction between the two fluorine atoms of 125 favoring a conformation that projects the C–F dipoles in a similar direction, reflected in the higher dipole moment of 1.63 D compared to 1.16 D for the geminal arrangement in 123. For the butyl series 127129, the vicinal difluoro-substituted compound 129 was less lipophilic than the geminal-substituted analogues 127 and 128, which translated into modestly higher aqueous solubility. Indeed, the Log P value measured for 129 was only slightly higher than that for the vicinally substituted homologue 125 despite the presence of the additional CH2 moiety, providing some instruction on how to deploy fluorine to advantageously modulate physical properties. The metabolic stability of the compounds in liver microsomal preparations was also evaluated, and while there appeared to be some enhancement associated with increased fluorination, the results were less than definitive.(81)
Table 12. Physicochemical Data Associated with the Series Fluorinated 3-Alkyl Indole Derivatives 121129
A practical consequence of the effect of a considered deployment of fluorine patterning on the solubility of a compound can be appreciated by comparing the properties of the homologous Mycobacterium tuberculosis (Mtb) inhibitors 130 and 131.(82) While both compounds are effective Mtb inhibitors that act by an unknown mechanism, the aqueous solubility of the CF2H-substituted compound 131 was more than 20-fold higher than the CF3 homologue 130 despite a modest increase in the measured value of Log P.

Replacing Hydrogen by Fluorine in Aromatic Rings

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Aryl Fluoride Derivatives and Metabolism

The judicious substitution of a hydrogen atom in aromatic and heteroaromatic rings by a fluorine atom can exert a significant impact on the properties of a molecule that are of beneficial interest in both drug design and development. An early focus of the introduction of fluorine to aromatic rings was as a tactic to slow metabolism, although fluorinated rings are still subject to metabolic modification by CYP 450 enzymes and fluorine has been shown to undergo the NIH shift.(83) A particularly interesting and complex example of metabolism associated with a fluorophenyl ring is provided by the hepatitis C virus (HCV) NS5B polymerase inhibitor tegobuvir (132), which was discovered using a phenotypic cell-based screen.(84a) The fluorination pattern of this chemotype is a critical determinant of antiviral activity, illustrated by the SAR associated with 133136 (Table 13), which were only understood as the result of a careful mechanistic analysis.(84b,c) Resistance mapping with 132 identified the NS5B polymerase as the antiviral target in the cell-based screen, but the compound was not a direct inhibitor of the enzyme in biochemical assays.(84b) Western blotting analysis of replicon cells treated with 132 revealed the presence of both the natural NS5B polymerase protein and a related protein with a molecular mass that was 820 Da higher. The modified NS5B protein represented the addition of one molecule of a metabolite of 132 that had lost one fluorine atom and acquired GSH. The antiviral activity associated with 132 was reversed by CYP 450 inhibitors, and this activity was subsequently narrowed to CYP 1A1 as the activating enzyme. The proposed metabolic pathway presented in Scheme 4 relies upon metabolism of 132 to the intermediate epoxide 137, which readily loses fluoride in a process presumably assisted by an electronic interaction with the imidazo[4,5-c]pyridine heterocycle, leading to the generation of the enone 139. This molecule offers two electrophilic sites that can react with GSH, with pathways A and B leading to the putative metabolites 140 and 141. However, GSH attack at the more hindered site outlined by pathway C would generate a molecule that retains electrophilicity and is capable of reacting with either GSH or a cysteine residue of the HCV NS5B protein. While the identity of the reactive cysteine in HCV NS5B was not definitively determined, Cys366 was suggested as a potential candidate because it is proximal to the active site of the enzyme, and compounds that react with this residue are documented as inhibitors of the enzyme.(84b,d)
Table 13. HCV GT-1b Replicon Inhibitory Activity of NS5B Inhibitors 133136

Scheme 4

Scheme 4. Metabolism of 132

Aryl Fluorides: Membrane Permeability and P-gp Recognition

Substitution of a hydrogen atom by fluorine to introduce an intramolecular interaction with a pendent N–H has been exploited to enhance membrane permeability following the seminal observations made with the two series of inhibitors of the coagulation enzyme factor Xa (FXa) summarized in Table 14.(85) Caco-2 cell permeability was improved by substituting the hydrogen atom ortho- to the anilide N–H, illustrated by comparing the MMPs 145/146, 147/148, and 149/150. These observations were attributed to an electrostatic interaction between the F atom and the proximal N–H that shields the H-bond donor properties, important to both passive permeability and recognition by P-gp.(86,87) That the effect was not a function of the electron withdrawing properties of the substituent was illustrated by the poor membrane permeability associated with the linear nitrile moiety incorporated into 151. This structural motif is well-represented in the medicinal chemistry literature and is particularly prevalent in kinase inhibitors.(4a)
Table 14. Caco-2 Cell Permeability Values Associated with the Two Series of FXa Inhibitors 145148 and 149151
This phenomenon is not restricted to anilides but is also observed in benzamide derivatives and the presence of a proximal fluorine atom to interact with these H-bond donating functionalites are common in drug candidates, particularly kinase inhibitors. The effect of intramolecular interactions of this nature has been explored more explicitly by comparing the permeability properties in a parallel artificial membrane permeability assay (PAMPA) of 27 MMPs of N-phenylamides that differ by only a fluorine for hydrogen atom exchange (Figure 8A).(88) In 12 of the 27 cases examined, replacing the ortho- hydrogen by a fluorine atom led to an increase in permeability of ≥ +0.3 log Pe. The alternate arrangement represented by the benzamides depicted in Figure 8B was also examined by evaluation of 15 MMPs, of which 9/15 exhibited an increase in the permeability coefficient of ≥ +0.3 log Pe. A simple increase in lipophilicity was not the source of the enhanced membrane permeability because there was no demonstrable effect with meta-substituted fluorinated compounds. Moreover, the observation that introducing a fluorine atom had no effect in six out of the total of the 42 MMPs examined emphasized the contextual nature of this phenomenon. An analysis of the motifs depicted in Figure 8 in the Cambridge Structural Database (CSD) identified a number of examples where there were close contacts between fluorine atoms and the pendent N–Hs that stabilized the molecular conformation.(88)

Figure 8

Figure 8. Core structures of MMPs of N-phenylamides and benzamides examined in a PAMPA.

Another practical illustration of the value of engaging an NH by a proximal fluorine is provided by observations in the series of β-hydroxyethylamine-based inhibitors of the aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE-1).(89) The lead inhibitor 152 exhibited potent activity in a cell-based assay, but the brain/plasma ratio following oral administration to rats was low, attributed to P-gp-mediated efflux based on observations of compound performance in a human LLC-PK1 cell line, data that are summarized in Table 15. A potential solution to this problem was probed by introducing structural elements designed to interact with the acetamide N–H because of the known role of exposed N–Hs in P-gp recognition.(87) The methoxy moiety in 154, which is capable of establishing a conventional intramolecular H-bonding interaction with the N–H, exhibited 2-fold higher permeability and a 5-fold reduced efflux ratio while only modestly (2-fold reduction) affecting potency, data that contrasts with the properties of the iso-butyramide 153. The ortho-fluorobenzamide derivative 155 exhibited similar membrane permeability to 152 but P-gp recognition was reduced almost 20-fold based on the efflux ratio, while the data for 156 suggest that an alkyl fluoride can perform similarly. These observations are consistent with an interaction between the fluorine atoms and the N–H along with a reduction in the basicity of the C═O oxygen atom that masks these elements from the external environment and which is believed to compromise P-gp recognition.
Table 15. BACE-1 Inhibitory Activity, Membrane Permeability Data, and Efflux Ratios for 152156
These effects were also manifested in the series of cyclic amidine-based BACE-1 inhibitors 157160 in which the exocyclic NH2 engaged the catalytic residues Asp32 and Asp228 of this aspartyl protease.(90) The lead compound 157 exhibited limited CNS penetration due, in part, to P-gp-mediated efflux, with a ratio of 12 determined from Papp values in Caco-2 cells. The introduction of a fluorine substituent in the peri position ortho- to the amidine carbon atom of 157 reduced the pKa by 1.3 units from 8.4 to 7.1 in 158, a structural modification that increased membrane permeability while reducing the efflux ratio by almost 4-fold (Table 16). In this example, the positive effect on permeability was amplified in the matched pair of homologues 159 and 160, attributed to a weak interaction between the fluorine atom and one of the hydrogen atoms of the NH2 that reduces the number of H-bond donors available to the environment. In addition, the solvation energy of the fluoro derivative was calculated to be less negative than for the hydrogen analogue, while the combination of electronic and steric effects was proposed to shield the polar nitrogen atom from the environment. In addition to the improvement in permeability and efflux ratio, BACE-1 inhibitory potency was retained for this series and an X-ray cocrystal structure of a close analogue of 160 revealed that the fluorine atom interacted with the carboxylic acid moiety of the catalytic Asp228, the side chain hydroxyl of Thr231, and three water molecules, with O to F distances that ranged from 2.9 to 3.3 Å.(90)
Table 16. BACE-1 Inhibition, Membrane Permeability, Efflux Ratio, and pKa Values for 157160
 R1R2BACE-1 IC50 (nM)Papp (10–6 cm/s)efflux ratiopKa of conjugate acid
157HH5003.4128.4
158FH158123.17.1
159HCF31340.13>10ND
160FCF3241390.66.9

Aryl Fluorides and Conformation of Proximal Substituents

A fluorine atom ortho- to the NH of an anilide also influences conformation, an effect exploited to illuminate the topology of the pharmacophore associated with the spiroindane-based calcitonin gene-related peptide (CGRP) receptor antagonist 161, which was evaluated as a potential therapeutic agent for the prevention of migraine attacks.(91) Although the oral bioavailability of 161 was reasonable, the PK profiles of more potent analogues were inferior, attributed to a high polar surface area (PSA) limiting absorption and focusing attention on replacing the central amide moiety with a less polar bioisostere. Modeling studies indicated a preference for coplanarity between the amide and spiroindane cores, with the lowest calculated energies observed at the two topologically divergent conformations of 0° and 180°. The preferred binding topology was probed by separately replacing each of the H atoms ortho- to the anilide by a fluorine to afford 162 and 163. It was anticipated that these substitutions would stabilize the complementary topologies depicted by the combination of an attractive electrostatic interaction between the N–H and fluorine and repulsive effects between the C═O oxygen and fluorine atoms due to steric and electrostatic considerations. Biological evaluation of isomers 162 and 163 demonstrated a 10-fold difference in CGRP receptor affinity favoring the extended conformation represented by 162, a hypothesis corroborated by the synthesis of the fused ring compound 164 that constrains the topology in an unambiguous fashion and preserves binding affinity.(91)
GPR119 agonists have been explored for their potential as a treatment for diabetes because they increase cAMP in in β-cells and stimulate insulin release, mimicking the effects of GLP-1. The introduction of a fluorine atom ortho- to the NH of the GPR119 agonist 165 afforded 166 with 8-fold improved potency, an effect that was not reproduced by the meta-fluoro analogue 167, which displayed potency similar to the progenitor (Table 17).(92) A similar SAR observation was made with the pair of related compounds 168 and 169, leading to the proposal that an intramolecular interaction between the fluorine and the N–H favored a planar conformation. This hypothesis was supported by the much weaker agonist activity associated with the N-methyl derivative 171 compared to the hydrogen analogue 170 and inspired the synthesis of bicyclic homologues as functional bioisosteres designed to constrain the preferred topology. The scaffold utilized in this exercise was of particular importance because the indoline 172 was found to be 10-fold more potent than the homologous tetrahydroquinoline 173.(92)
Table 17. hGPR119 Agonistic Activities Associated with 165169

Aryl Fluorination and Solubility

An interesting observation of the effect of replacing a hydrogen atom ortho- to an anilide N–H by fluorine is provided by the CGRP receptor antagonist 175, derived from the progenitor 174.(93) The measured aqueous solubility of 175 was determined to be over 30-fold higher than that of 174, an observation not well understood, with conjecture focused on the fluorine atom polarizing the adjacent N–H, thereby rendering it a more powerful H-bond donor to promote enhanced solvation. However, this phenomenon may contribute to the poor membrane permeability and oral bioavailability associated with 175, which led to a focus on intranasal drug delivery for the treatment of migraine.(93)

Fluorine Mimicry with Nitrogen-Based Lone Pairs of Electrons

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Aromatic Fluoride and Azine Mimesis

The similarity of the dipoles of fluorobenzene and azine heterocycles has been recognized as a potential drug design element, and this bioisostere concept has been explored in several settings, with the results exhibiting a dependence on context.(4g,94−99) The dipole relationships between fluorobenzene and pyridine, 1,2-difluorobenzene and pyridazine, and 1,3-difluorobenzene and pyrimidine are depicted in Figure 9. Using a simpler metaphor of structural analogy, the electron density associated with the fluorine atoms may be equated with the lone pairs of electrons associated with the heteroatoms of the heterocycles. There are, however, some limitations to the isosteric relationship because the experimental dipole moments determined for fluorobenzenes are less than those measured for the analogous azine heterocycle.(99) Notably, the addition of the third fluorine atom in 1,2,3-trifluorobenzene increases the predicted dipole moment compared to either the 1,2- or 1,3-difluoro isomer, enhancing this aspect of mimicry with pyridine and pyrimidine.(100)

Figure 9

Figure 9. Comparison of the dipole moments and vectors of difluorinated benzenes and azines.

Bioisosterism between an aryl C–F and an azine C–N bond was examined as a means of addressing developability issues in a series of α2/α3 subtype-selective GABAA agonists, explored as a potential treatment for anxiety.(95) Comparison of the receptor binding data accumulated for the MMPs 176/177 and 178/179 demonstrated effective bioisosterism between a C–F bond and a heterocyclic nitrogen atom in this context (Table 18). Of particular interest, 178 exhibited a poor PK profile due to the formation of the N-oxide at the exposed pyridine nitrogen atom in vivo. By replacing the ring nitrogen atom with a C–F moiety in combination with switching the other C–F to a nitrogen atom, both Log P and potency were maintained, while the PK profile was improved because the steric encumbrances surrounding the nitrogen atom in 179 interfered with N-oxidation. This type of structural isosterism may also be of value as a means of avoiding the CYP inhibition that is often associated with sterically exposed pyridine nitrogen atoms or mitigating susceptibility to aldehyde oxidase-mediated metabolism.
Table 18. SARs Associated with a Series of GABAA α2/α3 Subtype-Selective Agonists 176179
In the related GABAA agonist 180, where the imidazo[1,2-a]pyrimidine heterocycle functions as an interesting and effective bioisostere of the pyridazine ring of 176179, replacement of the nitrogen atom in the six-membered ring with a C–F moiety led to improved potency.(95b) This was illustrated by comparing the profiles of 182 with the pyridine prototype 180 and the C–H analogue 181, with 182 offering equivalent potency at both the α1 and α3 subtype receptors similar to 180 but with slightly higher efficacy at the α3 receptor and lower efficacy at the α1 subtype (Table 19). In this particular example, this was the targeted biochemical profile. In contemplating the design of 182, this study conducted what has probably been the most detailed analysis of C–F/azine bioisosterism. After careful consideration of the calculated and measured physicochemical properties of the abbreviated core heterocycles 183185 compiled in Table 20, the C–F derivative 185 was determined to more closely resemble the aza analogue 183 based on dipole and electrostatic potential mapping. Moreover, 183 and 185 express similar pKa values that are 2 units lower than for the C–H homologue 184, adding further to their functional resemblance; however, the Log D7.4 value for 185 is closer to that of 184 than the more polar 183.(95b)
Table 19. SARs and Receptor Selectivity Associated with the Series of GABAA Agonists 180182
 Xα1 Ki (nM)α3 Ki (nM)α1 efficacy (% chlordiazepoxide)α3 efficacy (% chlordiazepoxide)μ of core (D)
180N0.710.4760795.10
181C–H4.355.1635613.37
182C–F0.200.32341044.52
Table 20. Calculated and Measured Properties for 183185a
 Xcalculated dipole (D)measured pKameasured Log D7.4
183N3.37 (R = CH3)4.9 (R = H)–0.2 (R = H)
184C–H5.10 (R = CH3)6.9 (R = H)0.8 (R = H)
185C–F4.52 (R = CH3)4.9 (R = H)0.9 (R = H)
a

Structures were built and energy minimized using the Merck Molecular Mechanics Force Field (MMFF). The dipole values were extracted from an AM1 semiempirical calculation.

In the MEK inhibitor 186, the fluorine atom ortho- to bromine was observed to engage the backbone N–H of Ser212, a stabilizing drug–target interaction that was an important contributor to potency.(96) More conventional H-bond acceptors were explored in the context of the fused heterobicyclic derivatives 187 and 188 where the exposed pyridine and imidazole nitrogen atoms, respectively, interact with the N–H of Ser212. This illustrates a bioisosteric relationship between the C–F substituent of 186 and the heterocyclic nitrogen atoms of 187 and 188.(96)
Another example of an aryl C–F mimicking a pyridine atom was observed in a series of CHK1 kinase inhibitors.(97) The lead inhibitor 189, which was discovered using an affinity selection mass spectrometry-based automated ligand identification system screen, exhibited modest selectivity over CDK2 that was iteratively optimized into the more potent and selective pyridine-based inhibitor 190.(97) An X-ray cocrystal structure of 190 with the kinase revealed the important inter- and intramolecular interactions that contributed to the observed inhibitory potency (Figure 10).(97b) The key intermolecular interactions were catalogued as H-bonding between the pyridine ring nitrogen atom and the ammonium moiety of Lys38 and a H-bond between the amide C═O of the isoindolinone and the N–H of Cys87. In addition, there was a close association between the sulfur atom of the thiazole and the backbone C═O oxygen of Glu85, which approach each other at a distance of 3.0 Å, less than the 3.32 Å sum of the van der Waals radii for the two atoms and one of the limited number of reported examples of an intermolecular oxygen lone pair to sulfur σ* interaction.(31) In addition, the planar topography associated with 190 was stabilized by an intramolecular O to S interaction between the isoindolinone amide oxygen and the thiazole sulfur atom which are closer than the van der Waals radii, separated by just 2.87 Å. The potency and selectivity of 190 was matched by the fluorobenzene analogue 191, in which the fluorine atom was suggested to be involved in either a charge–dipole or H-bonding interaction with the side chain ammonium of Lys38.

Figure 10

Figure 10. Key interactions between CHK1 kinase and 190 in the cocrystal structure.

The effective pairing of the difluoro-benzimidazole 192 with cytidine in the context of RNA duplexes inspired an examination of the purine 193 and pyrrolo-pyrimidine 194 as functional mimetics.(98) These structural elements were incorporated as X into the 12-mer RNA 5′-CUU-UUC-XUU-CUU-3′, hybridized with the complementary strands 3′-GAA-AAG-YAA-GAA-5′ that incorporated each of the natural bases at Y and the melting temperatures of the duplexes determined. The results of this study are summarized in Table 21, with ParaFrag similarity scoring indicating that fluorobenzene was 45% similar to pyridine while chlorobenzene was of lower similarity at 27%. Interestingly, the ParaFrag scoring system indicated that in this context, a pyridine N-oxide was 25% similar while pyridone was just 22% similar to pyridine. Although these base pairings were less stable than the natural base pairs, 192 offers a relatively small energy difference compared to the natural bases, suggesting utility as universal base.(98)
Table 21. Melting Temperatures of 5′-CUU-UUC-XUU-CUU-3′ Hybridized with Complementary Strands 3′-GAA-AAG-YAA-GAA-5′
Fluorobenzene-azine bioisosterism has also been assessed in a series of mechanism-based inhibitors 195204 of cathepsin L although the results were less than definitive.(99) In 195204, the (hetero)aryl ring occupies the S3 pocket of cathepsin L and π-stacking and dipole–dipole interactions were observed between these compounds and the backbone amide bond of Gly67–Gly68 of the enzyme (Figure 11). However, while the fluorinated phenyl derivatives 195199 were effective mimics of their matched azine heterocycles 200204, there was no clear correlation between the dipole moment of the (hetero)aryl ring and inhibitory potency. This was attributed to the proximity of the adjacent Gly68–Leu69 amide bond which adopts a complementary topology to that of Gly67–Gly68 such that the dipole is aligned in the opposite direction, believed to be a source of interference with the targeted effect.(99)

Figure 11

Figure 11. Structures and cathepsin L inhibitory data for 195204.

Nitrogen Lone Pair Mimesis by an Alkyl Fluoride

An interesting suggestion of isosterism between the piperazine nitrogen atom of the 5HT1D and 5HT1B receptor ligand 205 and the C–F bond of the 4-fluoropiperidine analogue 207 has been invoked to explain the SAR observations.(101) Piperazine 205 is rapidly absorbed in rats, but the piperidine analogue 206 exhibited a poor PK profile attributed to the highly basic nature of the nitrogen atom of this compound. The 4-fluoropiperidine 207 is less basic and displayed a similar in vitro receptor binding profile to 205 and 206 but was associated with much improved absorption in the rat. These observations led to the suggestion that the C–F bond of 207 may be mimicking the unprotonated nitrogen atom of 205 based on electronic considerations and dipole moments, depicted in simplistic terms in Figure 12, although other factors may underlie the observed SAR effects.

Figure 12

Figure 12. Proposed relationship between a piperazine lone pair of electrons and the fluorine atom of a 4-fluoropiperidine ring.

Flourination and Potency

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The judicious replacement of a hydrogen atom by fluorine can exert a significant effect on both the potency and specificity of a molecule, and examples where this change either enhances or erodes the potency of a molecule have been described that, perhaps not surprisingly, are dependent upon context. In several examples, the potency-enhancing effects associated with the introduction of fluorine have been traced to intermolecular interactions between the fluorine and the carbon atom of C═O moieties that are characterized as multipolar in nature or to interactions of fluorine with proximal H-bond donors that may have an electrostatic basis.(102) However, other intermolecular interactions and effects involving fluorine atoms of ligands have also been described and are summarized in the next section.

Multipolar and Hydrogen Interactions of Fluorine with Proteins

A detailed mechanistic understanding of how the fluorination of alkyl groups can lead to enhanced potency is provided by 208215, a series of inhibitors of the binding of mixed lineage leukemia (MLL) to the tumor suppressor protein menin.(103) The fluorination patterns of the two alkyl moieties in 208215 were found to play important roles in modulating potency based on the systematic SAR studies that are compiled in Table 22. In the X-ray cocrystal structure of 211 bound to menin, each of the CF3 moieties were found to engage a backbone C═O of the protein in an orthogonal multipolar interaction. One F atom of the CF3CH2 substituent of 211 is 3.0 Å away from the backbone C═O of His181, while a fluorine atom of the CF3 that is bound to the thiadiazole is 3.4 Å away from the C═O of Met322. The effect of modulating the thiadiazole substituent was explored in the context of the homologous series 208211, where fluorination improved potency over the unsubstituted compound 208, with the exception of the monofluoromethyl derivative 209. The CHF2 analogue 210 was found to be equipotent with the CF3 derivative 211, and both were 9-fold more potent than the CH3 prototype 208. X-ray cocrystal structures revealed that 208, 210, and 211 bound to the protein in a similar fashion and that one of the F atoms of 210 was 3.2 Å from the C═O of Met322, while for 211, the fluorine to C═O carbon distance was 3.4 Å. However, for 209, the fluorine atom was oriented 38.5° out of the plane of the thiadiazole ring, located 3.7 Å away from the C═O carbon of Met322, a distance that was considered to be too remote for a productive multipolar interaction. The conformation of 209 was unanticipated, and a quantum mechanics (QM) analysis suggested that the second fluorine atom of 210 stabilized a conformation that allowed one of the fluorine atoms to engage the C═O of Met322. A similar SAR analysis conducted at the benzothienyl alkyl moiety in the context of the thiazolines 212215 revealed that the CH2F analogue 213 was almost 5-fold more potent than the CH3 prototype 212, while the CF2H analogue 214 offered an additional 4-fold potency improvement and this compound was just 1.5-fold weaker than the CF3 derivative 215, the optimal compound in this subseries.
Table 22. SARs Associated with Inhibitors 208215 of the Association of the Tumor Suppressor Protein Menin with MLL
These results of this study are consistent with an earlier seminal analysis of cocrystal structures in the Protein Data Bank (PDB), which revealed that fluorine atoms of ligands approached the backbone or side chain C═O moieties of a host protein closely (3.5 Å) and with an appropriate geometry in 16% (442 of the 2559) of the examples evaluated.(102) However, a few examples were highlighted where the effects of fluorine substitution were predicted to be beneficial but the experimental results were not supportive, emphasizing a need to be holistic when assessing the potential for orthogonal multipolar interactions between the fluorine atoms of a ligand and a protein.(102a) This is emphasized by an analysis of 247 matched pairs of compounds differing only by a fluorine for hydrogen exchange and for which there were both X-ray cocrystal structure data for the fluorinated compounds, and the fluorine atom was believed to be engaging in a multipolar interaction with the protein.(102b) In 67% of the examples in this data set, the fluorine was attached to a phenyl ring while the majority of the remaining compounds were CF3 derivatives. The results of the analysis revealed a modest advantage in potency for the fluorinated compounds compared to the hydrogen analogues. After ignoring 79 compounds that were within 2-fold of the 1:1 correlation line as being within experimental error, 123 (73%) of the remainder experienced an increase in potency associated with fluorine substitution while the other 27% exhibited a reduction in potency of more than 2-fold. The average improvement in the pIC50 value of the fluorinated compounds amounted to 0.36 log units, which translates to a free energy of binding advantage of approximately 0.5 kcal/mol. This reflects a modest but beneficial effect of fluorine substitution on potency that did not appear to be a function of increased lipophilicity; however, because the changes in both parameters were similar in magnitude, the effect on lipophilic ligand efficiency (pIC50 – Log P) was neutral.(102b)
A fluorine for hydrogen substitution in the benzamidine-based thrombin inhibitor 216 led to a 5-fold enhancement of potency for 218, which was found to be 3-fold more potent than the 4-Cl analogue 217 and 5–10-fold better than the other fluorination patterns probed by 219222.(104) An X-ray cocrystal structure provided an explanation for the observed SAR, which noted that the 4-fluoro atom was proximal to both the backbone C═O carbon atom (3.5 Å) and backbone C–H of Asn98 (F to N distance = 3.1 Å), as summarized in Figure 13, productive interactions that are not available to either 216 or 217.

Figure 13

Figure 13. Key interactions between inhibitor 218 and thrombin.

A more recent example of the importance of fluorination on potency is provided by a series of carbazoles that stabilize the Tyr220Cys mutant of the tumor suppressor protein p53.(105) In this inhibitor series, the CF3 homologue 224 exhibited 5-fold improved binding affinity compared to the hydrogen-substituted prototype 223, an observation rationalized by an examination of the X-ray cocrystal structure. As illustrated in Figure 14, each of the three fluorine atoms of 224 was found to engage the protein, with two establishing multipolar interactions with the backbone C═O moieties of Leu145 and Trp146 while the third fluorine atom was proximal to the thiol of Cys220, an association attributed to the combination of weak H-bonding and sulfur σ* interactions.(105)

Figure 14

Figure 14. Key drug–target interactions between the CF3 substituent of 224 and the p53 protein.

In a series of potent inhibitors of Bruton’s tyrosine kinase (BTK), a fluorine scan identified a site for substitution that led to a 10–40-fold enhancement of potency.(106) The effect of fluorination was most effectively exemplified by the comparison of the matched pair of BTK inhibitors 225 and 226 (RN-486), where the introduction of a single fluorine atom increased potency by an order of magnitude.(106a,b) An X-ray cocrystal structure of the ethyl homologue 227, where the fluorine atom contributed to a remarkable 400-fold increase in potency in a human whole blood (HWB) assay over the hydrogen-substituted prototype 228, provided some understanding of the SAR observation. The fluorine atom of 227 was observed to be close to the protonated amine of Lys430 (3.2 Å), the ortho C–H of Phe413 (3.4 Å), and a conserved H2O molecule (3.4 Å), as captured in Figure 15.(106a) Of note with respect to developability issues, while the cyclopropyl substituent in these analogues replaced a metabolically labile tert-butyl element, subsequent studies revealed a metabolic liability associated with the pyridone ring which was susceptible to CYP 450-mediated bioactivation and trapping by GSH, attributed to an initial epoxidation of the C-5,C-6-double bond. This problem was relieved by further optimization in which the pyridone ring was replaced by a pyridazin-3-one heterocycle but not when a pyrazine-2-one was used as the scaffold.(106c)

Figure 15

Figure 15. Key drug–target interactions between inhibitor 227 and BTK.

The CF3 substituent in 230, an inhibitor of the Q0 site of the cytochrome bc1 complex, enhanced potency by an order of magnitude when compared to the CH3 prototype 229.(107) An X-ray cocrystal structure of 230 with the chicken enzyme revealed close contacts (2.45–2.98 Å) between the fluorine atoms and two hydrogen atoms of Pro270, three hydrogen atoms of Ile146, and two hydrogen atoms in each of Tyr278 and Phe274 of the protein.(107)

The CF3 Moiety and Tetrel Bonding

A weak but nevertheless interesting interaction between the CF3 moiety and electron rich centers of proteins (CO2, amide carbonyl, and the oxygen atoms of serine, threonine, and tyrosine) that involves tetrel (CF3···O) bonding has recently been catalogued.(108) Molecular electrostatic potential (MEP) mapping of perfluorotoluene revealed a π-hole associated with the aromatic ring calculated to be +32.9 kcal/mol and a small region of positive potential at the sp3 carbon atom that characterizes a σ-hole that was calculated to be +16.9 kcal/mol (Figure 16).(108) The larger MEP value of the π-hole suggested that the dominant interactions of electron rich species with perfluorotoluene would be at this site, substantiated by calculations of the interaction energies of the π- and σ-holes with NH3, the carbonyl oxygen atom of acetone, formic acid anion, and phenoxide. The geometry of the interaction of electron rich species with the σ-hole associated with the CF3 substituent is highly directional in nature, optimal at an angle of 180° to the Ar-sp3 carbon bond.

Figure 16

Figure 16. Calculated energies of the σ-hole and π-hole associated with perfluorotoluene.

To develop insight into the contribution of this interaction in protein–ligand structures, a search of the PDB was conducted using parametric restraints that required a resolution factor of ≤3.0 Å, a distance between the carbon atom of the CF3 substituent of a ligand and the oxygen atom of the protein of less than 3.37 Å (the sum of the van der Waals radii of the two atoms: 1.7 Å for C and 1.52 Å for O) and an X–C···O angle of >160°. This process identified eight complexes where the carbon to oxygen distances ranged from 2.59 Å in the case of 231 interacting with the side oxygen atom of Asn97 of macrophage migration inhibitory factor to 3.35 Å for the Asp312B side chain carboxylic acid of the Arg140Gln mutant of mitochondrial isocitrate dehydrogenase 2 (IDH2) interacting with AGI-6780 (232).(109,110a) Two examples were examined in detail as illustrative of the phenomenon: the IDH2 inhibitor AG-221 (234) in complex with the enzyme and niflumic acid (235) in complex with the NmrA-like family domain containing protein 1 NMRAL1.(109,110b,111) The key aspects of drug–target interactions between 234 and 235 and their protein partners are captured in Figures 17 and 18, respectively. In the case of 234, the side chain carboxylate of Asp312 interacted with the CF3 of the inhibitor, while for 235, the hydroxyl O atom of Tyr246 was the partnering element. It was suggested that a potential indicator of the contribution of tetrel bonding to the interaction of 234 with IDH2 is provided by the profile of the des-CF3 derivative 233 which is 2-fold weaker; however, because this is data from a cell-based assay, it represents at best an imprecise index.

Figure 17

Figure 17. Key interactions between 234 and IDH2 in the cocrystal stucture.(110b)

Figure 18

Figure 18. Key interactions between 235 and the NmrA-like family domain containing protein 1 NMRAL1 in the cocrystal complex.(111)

Indomethacin (236) is a potent but nonselective inhibitor of the COX-1 and COX-2 enzymes, a profile that can be modified by fluorination of the 2-methyl substituent, illustrated by 237, which is a selective but 2-fold weaker inhibitor of COX-2 (Table 23).(112) Detailed kinetic studies revealed a Ki for human COX-2 of 13 μM for 236 and 1.5 μM for 237, while studies with a series of site-directed mutant enzymes indicated that the two compounds very likely bound to the enzyme in a similar fashion. Modeling studies suggested that the CF3 moiety of 237 filled a small hydrophobic pocket in the enzyme in a differential fashion, as detected by differences in inhibitory potency toward mutant COX-2 enzymes. In particular, the inhibitory activity of 237 toward the Val523Ile COX-2 mutant enzyme was reduced by more than 15-fold compared to a smaller 3.7-fold reduction for 236. However, because in the cocrystal structure Val523 is located proximal to the 5-OCH3 moiety of 236, the data were interpreted as being the result of the larger CF3 substituent causing displacement of the heterocyclic core toward the center of the binding pocket. This arrangement was postulated to induce a more significant steric clash between the 5-OCH3 substituent and the larger isoleucine side chain of the mutant enzyme.(112)
Table 23. Cyclooxygenase Inhibitory Profile of 236 and Its Fluorinated Homologue 237
 236237
RCH3CF3
ovine COX-1 IC5027 nM>100 μM
mouse COX-2 IC50127 nM267 nM
Another example of the introduction of a CF3 moiety contributing to increased potency is provided by the series of HCV NS3 protease inhibitors 238240, where both the intrinsic enzyme inhibitory potency and the antiviral activity in cell culture exhibited a dependence on the absolute configuration of the trifluoromethylated carbamate moiety that projects into the S4 subpocket of the enzyme, data that are summarized in Table 24.(113) In the absence of cocrystal structure data, rationalization of the observation focused on modeling studies that placed the CF3 moieties of the two diastereomers in different interactive relationships with the enzyme, with that of 240 suggested to exhibit a closer contact with the protein.
Table 24. SARs Associated with HCV NS3 Protease Inhibitors 238240a
a

Biochemical enzyme inhibition assay. Cell-based HCV replicon assay.

Fluorination patterning has been shown to play an important role in modulating both the potency and species selectivity of triazolopyrimidine-based inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (Pf DHODH) that have been probed as therapeutic agents for the treatment of malaria.(114) While the prototype triazolopyrimidine 241 was inactive in both biochemical and cell-based assays, the introduction of a para-CH3 substituent to the phenyl ring afforded the homologue 242 as a compound exhibiting modest inhibitory activity in both assays (Table 25). However, the CF3 analogue 243 was 15-fold more potent than 242, while the introduction of a CH3CH2 at C-12 (244) improved potency by a further 3–5-fold. In these compounds, the aniline N–H engages His185 in the active site of the enzyme in a H-bonding interaction that is a source of selectivity toward the malaria enzyme over the human homologue. The binding modes of these compounds differ between the two enzymes, with the N–H engaging His56, the residue in the human enzyme equivalent to His185, via the intermediacy of a H2O molecule. Additional optimization focused in fluorination of the C-12 substituent to give 245 which inhibited Pf DHODH with an IC50 value of 38 nM and was active in the cell-based assay with an EC50 value of 10 nM. The in vitro antimalarial profile of the SF5-containing DSM-265 (246) was similar to that of the CF3 analogue DSM-267 (245), and these two compounds offered an optimal compromise between potency and metabolic stability for the series of 4-substituents that were examined. However, in an animal model of infection, 246 offered a potency advantage while a more linear dose-exposure profile was observed in rats, leading to its selection as a candidate for clinical evaluation. The IC50 values for Pf DHODH inhibition were 33 nM for 246 and 38 nM for 245 and both compounds weak inhibitors of the human enzyme, IC50 values >100 μM; however, rodent enzymes were found to be more susceptible, with the IC50 values for mouse and rat measured as 2.3 and 2.7 μM, respectively, for 246, and 24 and 7.2 μM for mouse and rat, respectively, for 245. Interestingly, the species specificity of inhibition was found to be highly sensitive to the fluorination pattern of the aniline ring with the additional fluorine atoms ortho- to the CF3 substituent of analogues of 243245 enhancing inhibition of the mammalian enzymes by 5–100-fold. This phenomenon was attributed to an increase in the entropic contribution to binding as a consequence of favorable hydrophobic interactions established between the fluorinated inhibitors and leucine residues in the mammalian enzymes, suggested as evidence that fluorination of a molecule can enhance binding to the lipophilic pockets of proteins.(114)
Table 25. SARs Associated with Triazolopyrimidine-Based Pf DHODH Inhibitors 241246
 RXR1Pf DHODH IC50 (μM)Pf 3D7 cells EC50 (μM)
241 (DSM12)HCHH>200>100
242 (DSM97)HCHCH34.26.4
243 (DSM74)HCHCF30.280.34
244 (DSM280)CH3CH2CHCF30.0870.058
245 (DSM267)CH3CF2CHCF30.0380.010
246 (DSM265)CH3CF2CHSF50.0330.046
An unusual effect that was observed when aryl hydrogen atoms were replaced with fluorine is found by comparing the activity profiles of the Aurora A kinase inhibitors 247249.(115) The mono-fluoro compound 248 was 2-fold more potent than prototype 247 in both a functional and binding assay, while potency was further enhanced by introducing a fluorine atom to the pyrimidine ring to give 249. However, the most interesting observation arose from an analysis of X-ray cocrystal structures which revealed substantially different biochemical modes of inhibition for 247 compared to 248 and 249. In the X-ray cocrystal structure of Aurora A kinase with 247, the DFG loop was in the active DFG-in conformation, stabilized by an interaction between Asp274 and Lys162. Attempts to soak 248 into crystals of Aurora A kinase were unsuccessful, suggesting that binding required changes to the crystal lattice. After developing conditions for cocrystal formation, the X-ray structures of both 248 and 249 revealed that the DFG loop had flipped to the DFG-out conformation based on rotation about the Ala273 amide carbonyl (Figure 19). In this conformation, Asp274 was rotated ∼100° away from the ATP binding site and there was substantial rearrangement of intramolecular interactions within the protein. This effect on enzyme conformation was also observed with the chloro-, bromo-, and cyano- homologues of 248 but not with the CF3-, CF3O-, or phenyl-substituted analogues, arguing against a steric effect as the source. In the cocrystal structure, the fluorine atom was 3.8 Å away from the carbon atom of the CH3 side chain substituent of Ala273, with the C–F bond aligned almost collinearly with the vector of the Cα–Cβ bond. For Cl and Br, the measured distances were shorter at 3.4 Å, but the geometry remained collinear. These observations were interpreted in the context of an induction of a dipole in the Cα–Cβ bond of Ala273 by the C–F dipole of the ligand that was transmitted to the amide C═O, thereby facilitating rotation of the peptide backbone, as summarized in Figure 19.

Figure 19

Figure 19. Proposed dipole interactions between 248 and Aurora A kinase leading to a conformational change in the DFG loop of the enzyme.

Fluorine and the Modulation of the Basicity of Amines

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The high electronegativity associated with a C–F bond has made introduction of fluorine a useful approach to modulate the basicity of proximal amines without introducing additional polarity, with effects that are quantitatively predictable based on the number of fluorine atoms and their connectivity with the nitrogen atom.(116) A careful analysis of the fluorination pattern of a series of tetrahydroisoquinoline-based inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme that methylates norepinephrine to produce epinephrine, led to the identification of compounds with improved selectivity because binding to the α2 adrenoreceptor subtype was a problem inherent to this chemotype.(117) As summarized in Table 26, the successive introduction of fluorine atoms to the CH3 moiety of 250 led to stepwise reductions in the basicity of the tetrahydroisoquinoline heterocycle in homologues 251253. Fortunately, PNMT inhibitory potency proved to be less sensitive to a reduction in basicity than did binding to the α2 adrenoreceptor, allowing the sought-after balance of selectivity to be achieved with the CHF2 derivative 252.
Table 26. Basicity, PNMT Inhibition, and α2 Adrenoreceptor Affinity for the Tetrahydroisoquinolines 250253
 RpKa of conjugate acidKi PNMT (μM)Ki α2 (μM)PNMT selectivity
250CH39.290.0171.165
251CH2F7.770.0236.4280
252CHF26.120.0942302400
253CF34.333.2>1000>310
An interesting application of the effect of modulating amine basicity by replacing a hydrogen atom with a fluorine is found in 255, a mono-fluoro analogue of the potent μ opioid agonist fentanyl (254).(118) The design of 255 explored the hypothesis that peripheral μ opioid receptors are upregulated in painful syndromes and contribute to the sensation of pain. In addition, tissues at sites of damage that produce pain are associated with inflammation and a lower pH, providing a unique environment that could be taken advantage of to modulate the selectivity of action of 254 in a fashion that would spare receptor activation in normal tissues. The hypothesis was based on the understanding that the protonated form of the highly basic 254, pKa > 8, that predominates at physiological pH is that recognized by the receptor where it engages Asp147. The introduction of a single fluorine atom to the piperidine ring of 254 to afford 255, evaluated as a mixture of diastereomers, reduced the measured pKa value to 6.8 and, as such, this compound would be substantially protonated only at pH values that are below those characteristic of normal physiological conditions. Binding experiments conducted in human embryonic kidney cells transfected with the μ opioid receptor indicated that the affinity of 254 was independent of pH with the Ki value at pH = 7.4 = 1.1 nM while 255 bound less potently at physiological pH, Ki = 17.9 nM, than pH = 5.5, Ki = 7.3 nM, and pH = 6.5, Ki = 3.7 nM. This profile would favor binding of 255 to the μ opioid receptor only at lower pH values, providing a measure of selectivity based on local tissue conditions. Thus, 255 was anticipated to activate the μ opioid receptor at the source of pain generation where the pH is believed to be lower than 7.4. In a series of in vivo studies, 255 produced analgesia in rats in an injury-restricted fashion in two different models of inflammatory pain that, in contrast to 254, was reversed by a peripherally active, non-CNS penetrant μ opioid receptor antagonist. Consistent with the proposed selectivity profile, 255 was devoid of the respiratory depression, sedation, and constipation side effects associated with 254 and exhibited reduced addiction potential as measured by a conditioned place preference evaluation.(118)
In a series of inhibitors of kinesin spindle protein (KSP), a member of a family of motor proteins that was explored as a mechanism for the treatment of taxane-refractory solid tumors, it was determined that P-gp recognition was sensitive to the basicity of a core piperidine moiety.(119) A pKa value of 6.5–8.0 was determined to be optimal for maximal efficacy in a tumor cell line by reducing efflux, and this was achieved by both the N-cyclopropyl and N-fluoroethyl derivatives 256 and 257, respectively. However, 256 displayed time-dependent CYP 450 inhibition in vitro, a known liability of cyclopropyl amines, while evaluation of 257 in vivo revealed toxicity consistent with the release of fluoroacetic acid as a consequence of N-dealkylative metabolism. The solution to this problem was to install a fluorine atom in the piperidine ring where the effect on pKa was found to be sensitive to disposition, with the axial compound 258, which was selected for clinical evaluation, more basic than the equatorial isomer 259.(119a)
In the structurally related series represented by prototype 260, modulation of P-gp by fluorination of the primary amine-containing side chain identified both 261 and 262 as satisfactory solutions with efflux ratios of 3 and 5, respectively, compared to the much higher value of 1200 recorded for 260.(119b)
The introduction of a fluorine atom at the bridgehead position of the quinuclidine-based α7-N-acetylcholine receptor inhibitor 263 afforded 264, a compound with a 2.5 unit lower pKa value that effectively addressed the Caco-2 efflux problem associated with the more basic parent compound.(120) Unfortunately, this structural modification also resulted in a significant erosion in receptor recognition.
Control of basicity is also an approach that has been exploited to modulate the binding of inhibitors to the hERG cardiac potassium channel, a phenomenon that has been associated with the occurrence of arrhythmias in humans, and the induction phospholipidosis, off-target liabilities that have been suggested to possess overlapping pharmacophores.(121) For example, reduction in the electron density and Log P value of the pyridine heterocycle of the JAK3 inhibitor 265 was examined as an approach to reducing the affinity of this compound for the hERG channel.(122) As captured in Table 27, the installation of a fluorine atom in the piperidine ring reduced hERG binding by an order of magnitude without a significant change in the calculated Log P value that was accompanied by a 4-fold increase in potency for the (3S,4R) isomer 267 compared to prototype 265. The (3R,4R) isomer 266 was several fold less potent than 267 but was also poorly recognized by the hERG channel.
Table 27. JAK3 Inhibitory Potency, hERG Binding, and Calculated Log P Values for 265267
 RR′JAK3 IC50 (nM)hERG binding (μM)cLogP
265HH1.313.42.8
266FH1.7>1002.7
267HF0.3>1002.7
A fluorine for hydrogen exchange was also taken advantage of as an approach to modulate the basicity of the oxazine-based BACE-1 inhibitor 268 in order to improve membrane permeability and reduce P-gp-mediated efflux from the CNS compartment.(123) The amino oxazine ring system had been specifically selected as the scaffold to present the key amidine pharmacophore based on calculations conducted a priori that predicted moderate pKa values. However, the experimental pKa values revealed the predictions to be inaccurate, with measured values considerably higher than had been anticipated. This was exemplified by the prototype 268 for which the measured pKa was 9.6, over 3 units higher than the predicted value of 6.4 based on the calculations. After subcutaneous administration to mice, the measured brain levels for 268 were low and the compound was found to be subject to P-gp-mediated efflux in vitro. The introduction of several fluorinated elements to the oxazine ring was contemplated as a means of further refining the basicity, with C-2 selected as the optimal site based on an analysis of the X-ray cocrystal structure where this vector was directed toward the flap residues, offering potential to productively engage the protein. In the event, a simple 2-fluoro substituent proved to be the most effective modification, reducing the pKa value of the amino oxazine by 1.2–1.4 units. However, potency was shown to be dependent upon the absolute configuration of the newly introduced chiral center because the axial (2S)-isomer 270 was less potent and less basic (IC50 = 102 nM, pKa = 7.6) than the equatorial (2R)-isomer 269 (IC50 = 12 nM, pKa = 7.8). The reduced basicity enhanced the correlation between enzyme inhibitory potency and activity in the cell-based assay, which was attributed to reduced accumulation of compounds in the acidic endosomal compartment where BACE-1 is located. However, 269 exhibited low metabolic stability, and the more stable pyridine nitrile 271 was subsequently selected for evaluation in in vivo studies where a dose-related reduction in Aβ42 levels in CSF was observed, with a 90% decline measured following drug dosing at 2.5 mg/kg to dogs.(123)

N-CF3 Derivatives

N-Trifluoromethyl amines represent an emerging functionality that compromises the basicity of an amine but have only been cursorily explored as an element in drug design, presumably a function of issues associated with synthetic access.(124) A recent article has described a facile synthesis of N-CF3 derivatives using a mild preparative procedure that is compatible with late-stage functionalization. The developed process relies upon the reaction of an amine with (Me4N)SCF3 and AgF in CH3CN or CH2Cl2 and the N-CF3 derivatives of anilines, cyclic amines, and alkyl amines were prepared in good yield using this protocol. Included in the survey was the preparation of 272274 which are the N-CF3 analogues of the PDE-5 inhibitor sildenafil, the antifungal agent terbinafine, and the tricyclic antidepressant amitriptyline, respectively. Unfortunately, these compounds were not evaluated in the appropriate assays to determine if biological activity was preserved or in in vitro assays that would offer insight into drug developability properties and potential issues.(124)
The best documentation of an N-CF3 derivative that has been assessed biologically in vitro is provided by the quinolone 276, which was tested in the series of antibacterial assays summarized in Table 28.(125) The inhibitory profile of 276 toward both Gram-positive and Gram-negative bacteria was comparable to the N-CH3 homologue 275, with some possible advantage for 276 with respect to inhibition of P. aeruginosa.
Table 28. Antibacterial Activity Associated with the N-CH3-Substituted Quinolone 275 and Its N-CF3-Substituted Homologue 276
  Gram-positiveGram-negative
 RS. aureus SmithSt. pneumoniae type IIIE. coli NIHJ JC-2P. aeruginosa IID1210
275CH30.783.130.056.25
276CF30.396.250.051.56
The purine 277 was prepared as the sole N-CF3 derivative in a series of Cdk2 inhibitors, and this compound inhibited the enzyme with an IC50 value of 1 μM.(126) Unfortunately, the matching N-CH3 analogue that would allow a direct comparison was not made but the Cdk2-inhibitory activity of 277 was comparable to similar alkyl-substituted analogues in the broader series.

Fluorine and Carbonyl Bioisosterism

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A number of drug design initiatives have sought to take advantage of fluorine-containing functionality as bioisosteres of the carbonyl functionality. However, while there has been some focus on mimicking the amide functionality, which will be discussed later, there are examples of the use of fluorinated elements as bioisosteres of the carbonyl moiety of ketones, lactones, and carboxylic acids. In this section, representative examples are discussed that demonstrate functional bioisosterism in a range of biochemical contexts, with the underlying design principles in some cases supported by X-ray cocrystallographic data.

sp3 C–F as a C═O Bioisostere

Mimicry of C═O by a C–F is a function of the similarity between bond lengths, van der Waals radii and dipoles of the two functionalities and the electronegativity of oxygen and fluorine. A successful application of C═O/C–F bioisosterism can be found in studies with camptothecin (278), a naturally occurring alkaloid derivative that potently inhibits topoisomerase I and prevents tumor cell proliferation in vitro with EC50 values of <1 μM.(53b,127) However, in vivo applications of 278 are limited, in part, by the low chemical and metabolic stability associated with the lactone ring which is hydrolyzed rapidly to the inactive carboxylic acid derivative. Replacing the lactone C═O with an α-fluoro ether moiety was examined as a potential bioisostere based on an appreciation of the similarity of dipoles of the C–F and C═O bonds.(127) The (2R)-isomer 279 was a significantly less potent inhibitor of both topoisomerase I enzyme-mediated relaxation of supercoiled DNA and tumor cell proliferation in vitro than the (2S)-isomer 280. However, in assays measuring stability in H2O at pH = 7.4, the fluoro ether ring of 280 was found to offer superior performance when compared to the lactone 278. Lactone 278 was degraded by >50% after 6 h of incubation compared to a loss of just 4% for 280, with a similar profile observed in phosphate buffer. The antiproliferative potency of 279 was fully restored to the levels offered by 278 by decoration of the quinolone core, with the C-7 cyclohexyl derivative 281 optimal. This compound demonstrated dose-related inhibition of tumor growth in two xenograft models following IP administration of doses of 2–4 mg/kg, with efficacy comparable to topotecan (282), a camptothecin derivative, at a dose of 0.5 mg/kg. Notably, administration of 281 at 2 mg/kg was not associated with the weight loss observed with 0.5 mg/kg doses of 282.

Fluoro Alkenes and Aromatic Fluorides as C═O Bioisosteres

Fluoro- and trifluoromethyl-alkenes and chloroalkenes have been proposed as potential amide bioisosteres based on the topological, steric, and electronic relationships illustrated in Figure 20, and some of these structural elements have found application in the design of both small molecule drugs and peptidomimetics.(8,128−132) However, while the geometries are similar, the dipoles associated with the fluorinated and chlorinated olefins are of a lower strength when compared to an amide, more comparable to an aldehyde or ketone, and although the dipole vectors are similarly aligned, DFT calculations indicate that a chloroalkene more closely approximates an amide than a fluoroalkene.(133,134)

Figure 20

Figure 20. Dipole moments and vectors that illustrate isosterism between an amide moiety and fluorinated alkene derivatives that contrasts with simpler alkenes.

Examples of Fluorinated Alkenes As Amide Bioisosteres

An example where a fluoroalkene functions as an effective amide replacement when embedded in a peptidomimetic background is provided by studies with Leu-enkephalin (283), a pentapeptide that activates the δ-opioid receptor but fails to produce analgesia in vivo due to poor PK properties.(131) The ester 284 and thioamide 285 retained δ-opioid receptor activity, indicating that a H-bond donor at this site was not essential and inspired the design of the fluoro olefin 286. The potent activity of 286 confirmed the H-bonding hypothesis, while the weaker receptor binding affinity associated with the simple olefin 287 emphasized the importance of the fluoride atom for effective functional mimicry.
A fluoro alkene was also examined as a replacement for the amide moiety at the Tyr1–Gly2 junction as an approach to interfering with metabolism at this site.(132) The Leu-enkephalin analogue 288 demonstrated significant activity toward activating the δ- and μ-opioid receptors stably expressed in CHO cells, although the EC50 values were 60- and 45-fold higher, respectively, than for progenitor 283. However, differentiation was observed at the κ-opioid receptor where the activity of 288 was negligible compared to 283, which expressed an IC50 value of 80 nM.(132)
Both a fluoro- and a chloro-alkene were found to be effective amide mimetics when installed in a 36-residue peptide derived from the amino terminus of human parathyroid hormone (hPTH), where they were incorporated as part of a dipeptide element installed at the amino terminus.(134) Comparison of the matched pairs 289/290 and 291/292 indicates that in this context, the fluoro- and chloro-alkenes performed similarly with respect to binding to the PTH receptor and expression of full intrinsic activity as measured by cAMP production, with the exception of 289, which acted as a partial agonist (Table 29).(134b)
Table 29. hPTH Receptor Binding Data for 289292
A1-A2-Ser3-Glu-Ile-Gln-Leu-Met-His-Asn10-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg20-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp30-Val-His-Asn-Phe-Val-Ala-NH2
 XRbinding affinity to opossum kidney (OK-1) cells (pKD)cyclic AMP OK1 EC50 (nM) (intrinsic activity
289FCH38.29.1 (0.6)
290ClCH38.95.5 (1.0)
291FiPr8.94.4 (1.0)
292CliPr8.97.9 (1.0)
A fluoro-olefin was examined as a potential amide bioisostere in DPP-4 inhibitors in an attempt to confer resistance to cleavage by amidases or proteases, with 294 found to be 5-fold less potent than its matched amide 293, attributed to the weaker dipole associated with the former.(135) However, potency was enhanced by variation of both the P1 moiety and the pattern of substitution on the phenyl ring, with 295 a considerably more potent DPP-4 inhibitor. An X-ray cocrystal structure of 295 bound to the enzyme revealed a similar binding mode to an amide homologue, with the fluorine atom of the bioisostere proximal to the side chain N-Hs of Arg125 and Asn710, described as a H-bonding interaction.(135)
A conformational analysis of the symmetrical and potent HCV NS5A inhibitor daclatasvir (296) revealed that the most stable conformers were those stabilized by an intramolecular H-bond between the valine carbonyl oxygen atom and the imidazole N–H (distance = 2.2 Å).(136) This topography resembled that of a γ-turn and inspired the design of a fluoro-alkene amide bioisostere in which both of the valines of 297 were predicted to adopt a similar conformation, with the fluorine to imidazole N–H distance predicted to be 2.29 Å. In contrast, the analogue 298, in which the conformational constraint associated with the cylcopentane ring of 297 was relaxed, was predicted to exhibit a much lower propensity to adopt a γ-turn topography. In a GT-1b HCV replicon assay, although 297 was several fold weaker than 296, it still maintained subnanomolar inhibitory potency.(136a) However, in both GT-1a and GT-2a replicons, 297 was substantially (>2500-fold) less active than 296, demonstrating the heightened sensitivity of these two genotypes to structural changes in the molecule.(136b) The antiviral effects of 298 were of lower potency, lending some support to the fundamental design principle.
Fluorinated olefinic peptide nucleic acids 301 (F-OPAs), patterned after peptide nucleic acids 299 (PNAs), were prepared with adenine, thymidine, and guanine as the bases and incorporated into decameric oligomers for evaluation of the stability of the duplexes with complementary strands of DNA.(137) The stability, as determined by Tm values, was dependent upon the location of the nucleotide mimetic in the sequence, and while fully modified F-OPA decamers and pentadecamers formed parallel duplexes with complementary DNA, their stability was lower than either the peptide nucleic acid analogue 299 or OPA analogue 300.

Aromatic Fluorides as C═O Bioisosteres

An aromatic fluoride, which may be viewed as incorporating an embedded alkenyl fluoride, has been shown to effectively substitute for a lactam carbonyl moiety in several biochemical contexts. Prominent examples where a bioisosteric relationship is supported by X-ray cocrystal structure data have been provided by inhibitors of enzymes in the coagulation cascade, studies that have provided detailed insights into structural emulation.(138,139) Comparison of the MMPs 302 and 303, which are dual tissue factor VIIa (FVIIa) and thrombin (FIIa) inhibitors and prototype molecules in their respective series, provide an index of the level of functional mimicry, with the fluorophenyl moiety approximately an order of magnitude less potent in both enzyme assays.(138a,b) An X-ray cocrystal of the analogue 304 with FVIIa revealed that the fluorine atom was close to the N–H of Gly216 (N to F distance = 3.4 Å) in a fashion that was reminiscent of the H-bond observed between the carbonyl oxygen atom of the amide-based inhibitors (Figure 21).(138) In this structure, the iso-propyl-substituted aniline N–H of 304 donated a H-bond to the backbone C═O of Gly216, with the N to O distance measured as 3.4 Å.

Figure 21

Figure 21. Key interactions between and FVIIa and the benzamidine-based inhibitor 304.

Comparison of the data for the matched pair of thrombin inhibitors 305 and 306 suggests the potential for a bioisosteric relationship between the fluorophenyl and pyridine N-oxide moieties although the H-bonding properties of the two elements are considerably different, with the N-oxide moiety the more powerful acceptor.(139b,c,140)
A fluorobenzene motif has also been found to be an effective amide bioisostere when incorporated into allosteric inhibitors of the HCV NS5B RNA-dependent RNA polymerase, with 307 the prototype of the series.(141) The 2-fluoro derivative 309 was a potent inhibitor of NS5B biochemical activity in vitro, a profile that extended to the 2,4-difluoro homologue 310. However, the des-fluoro analogue 308 and the 3,4-isomer 311 were found to be less potent, data that collectively emphasized the importance of the topology of fluorine patterning and were concordant with the idea that the C–F moieties in 309 and 310 mimic the C═O of 307. An X-ray cocrystal structure of 309 with the NS5B enzyme revealed that hydrophobic interactions were dominant, with no specific interaction observed between the carboxylate element and the protein (Figure 22). However, the fluorine atom of 309 was close to the backbone NH of Tyr448 with a nitrogen to fluorine distance of 2.6 Å, while the hydrogen atom ortho- to the fluorine substituent was 2.9 Å from the backbone carbonyl oxygen atom of Ile447, a distance less than the sum of their van der Waals radii that was suggestive of a C–H H-bonding interaction.(140c,141)

Figure 22

Figure 22. Key drug–target interactions between 309 and the HCV NS5B polymerase protein.

In a series of non-ATP competitive MAP kinase kinase 1 (MEK1) inhibitors, the fused pyridone 312 exhibited an IC50 value of 38 nM.(142,143) Although clearly not a MMP, the difluorobenzene homologue RO4987655 (313) demonstrated high inhibitory potency toward the kinase, and this compound was advanced into phase I clinical trials.(144) An X-ray cocrystal structure of the bromobenzene derivative 314 bound to MEK1 was informative, revealing an intramolecular H-bond between the N–H and the C═O oxygen atom of the hydroxamic acid ester (Figure 23).(143,144) In addition, there was a halogen bonding interaction between the iodine atom and the backbone carbonyl oxygen atom of Val127 while the 4-fluoro atom was close to the backbone N–H moieties of both Ser212 and Val211.

Figure 23

Figure 23. Key drug–target interactions between MEK1 and inhibitor 314.

Several additional examples where there is evidence of a bioisosteric relationship between the C–F and C═O moieties have been described. In a series of pyridone-based fused tricyclic human androgen receptor (hAR) antagonists of which 315 is representative, examination of the potential of a bioisosteric relationship between the C–F and C═O moieties was adopted as an approach to understand which pyridone tautomer was responsible for the drug–target interactions.(145) The assays for assessing these compounds were based on a primary understanding of hAR binding affinity in a biochemical assay, while functional effects were determined based on inhibition of hAR-dependent transcriptional activity in mammalian CV-1 cells. While 8-amino and 8-alkoxy compounds were much weaker antagonists, small electron withdrawing groups at C-8 were preferred, with nitrile (316) and fluorine (317) optimal. In this context, there appears to be a bioisosteric relationship between the C═O, C≡N, and C–F moieties, and the data were proposed to support the concept that a H-bond acceptor is required at this site of the pharmacophore, leading to the suggestion that the active tautomer was that of the pyridone represented in 316 rather than the alternate hydroxy pyridine.(145)
A C–F bond has also been invoked as a C═O isostere in the context of the GABA aminotransferase inhibitors 318 and 319, where the carboxylic acid moiety was mimicked by a 2,6-difluorophenyl ring.(146) The fluorine patterning in 318 and 319, which are competitive inhibitors of GABA aminotransferase with Ki values of 11 and 6.3 mM, respectively, enhanced the acidity of the phenolic hydroxyl, which has a pKa value of 7.12 compared to 9.81 for phenol. The structural overlays presented in Figure 24 were used to illustrate the postulated isosteric relationship between the C–F bond of 318 and 319 and the C═O moiety of the carboxylic acid of 82.(146)

Figure 24

Figure 24. Structural overlays of 82 with 318 and 319 illustrating C–F and C═O mimicry.

These observations were the basis of the installation of a 2,6-difluorophenol moiety as a potential carboxylic acid bioisostere in a series of carbonic anhydrase inhibitors patterned after the carboxylic acids 320 and 321.(147) In the analysis of the matched pairs 320/321 and 322/323, the 2,6-difluorophenol offered a potency advantage that was further modulated by modifying the phenyl ring substituents of 322 (compounds 324 and 325) or by the introduction of the benzyl moiety, as in 326 and 327.(147)

Alkenyl Fluoride as an Enol Mimetic

Alkenyl fluorides have also been contemplated as mimics of enol-based intermediates in enzyme-mediated reactions.(148−150) The alkenyl fluorides 329 and 330 were prepared as mimics of the (Z) and (E) enol forms, respectively, of pregnenolone 328. These compounds were probed as inhibitors of steroid C17α hydroxylase/C17(20) lyase, which converts progesterone to androstenedione and 328 to dehydroepiandrostene, with extension to potential therapies for prostate cancer and hormone-dependent breast cancer which rely upon the production of androgens and estrogens, respectively.(148) The enol of 328 is thought to be an intermediate in the initial C17α hydroxylation step catalyzed by the dual acting enzyme. Incubation of 329 with cynomolgus monkey testicular C17(20) lyase at a concentration of 1 μM resulted in 49% inhibition of enzymatic activity, with the effect determined to be time-dependent because inhibition after 40 min of preincubation increased to 72%. By way of contrast, 330 was associated with 54% inhibition of C17(20) lyase activity at a concentration of 1 μM but with minimal evidence of time-dependence because the amount of inhibition was relatively constant, measured as 60% after a 40 min preincubation period.(148)
Other steroidal enzyme inhibitors where an alkenyl fluoride has been explored as a transition state mimic are the type I and type II 5α-reductases which convert testosterone (331) to the more androgenic dihydrotestosterone (333), with the enolate 332 a postulated intermediate (Scheme 5).(149) Finasteride 18 is a potent inhibitor of the type II 5α-reductase, IC50 = 1.2 nM but is a more modest inhibitor of the type I enzyme IC50 = 650 nM. The alkenyl fluoride 334 inhibited the type II 5α reductase with an IC50 value of 480 nM, 400-fold less potently than 18, and the type I enzyme with an IC50 value of 1300 nM, 2-fold weaker than 18. The alkenyl fluoride 334 was unique in the halogen series because the homologous chloride 335 and bromide 336 were inactive in both assays. In this context, the alkenyl fluoride moiety may be considered reflective of a bioisosteric relationship with both an enolate and an amide.

Scheme 5

Scheme 5. Metabolism of 331333 by Steroid 5α-Reductase
The α,β-dihydroxyacid dehydratase class of enzyme catalyzes the elimination of water from a dihydroxy acid to produce the enol 337, which is tautomeric with an α-keto acid, as summarized in Scheme 6.(150) The alkenyl fluoride 338 was prepared as a mimic of 337, a design principle successful to the extent that this compound inhibited the dehydratase with a Ki/Km ratio of 0.18, superior in this case to the simpler acrylate 339 and the amide 340, which was inactive.

Scheme 6

Scheme 6. Reaction Process Catalyzed by α,β-Dihydroxyacid Dehydratase

The 1,1-Difluoro Alkene Moiety as a C═O Bioisostere

The fluorine atoms of the 1,1-difluoroalkene moiety have been advocated in C═O mimesis, with the two fluorine atoms approximating the electron density associated with the lone pairs of electrons associated with the oxygen atom, although with similar dipole alignment of 30% lesser magnitude, as summarized in Figure 25.(151)

Figure 25

Figure 25. Isosteric relationship between formaldehyde and 1,1-difluoroethylene.

A pioneering examination of a 1,1-difluoroalkene as a C═O mimic was in the design of 341 as a substrate analogue of thymidine diphosphate (TDP)-6-desoxy-l-lyxo-4-hexulose (342) which is reduced to TDP-l-rhamnose (343) by the action of TDP-l-rhamnose synthase, a pathway summarized in Scheme 7.(152) The design premise was based on the underlying electronics of the C═CF2 moiety acting as a C═O mimic, with the anticipation that the addition of hydride to the olefin would occur with facility and in the same fashion as the addition to the ketone carbonyl. This mode of reaction was expected to generate an intermediate anion on a carbon atom that is adjacent to two fluorine atoms, setting up potentially unfavorable interactions with the fluorine lone pairs that would be destabilizing and precipitate either a structural rearrangement or the loss of fluoride to afford a reactive carbene species.(153)

Scheme 7

Scheme 7. TDP-l-rhamnose Synthase-Catalyzed Reduction of 342 to 343
In the event, incubating TDP-l-rhamnose synthase (1 μM) with a 6000-fold excess (6.1 mM) of 341, evaluated as a 3:1 mixture of α- and β-anomers, revealed that it acted as a poor but nevertheless kinetically competent substrate. However, irreversible inactivation of the enzyme was not observed; rather, the isolated products reflected the loss of one (344) or both fluorine atoms (345), an observation that was attributed to hydride addition to the exocyclic carbon atom which was favored over the alternative site of attack (Scheme 8). The resulting anion would be expected to decompose by elimination of fluoride, with the initially produced 344 also acting as a substrate for the enzyme, able to engage in a repeat of the reduction cycle that would lead to the completely defluorinated olefin 345, a process depicted in Scheme 8. Thus, in this context, the difluoro olefin of 341 does indeed act as a mimic of the ketone C═O but reverses the regioselectivity of hydride addition.

Scheme 8

Scheme 8. Postulated Reaction Pathway of 341 with TDP-l-rhamnose Synthase
A successful application of the 1,1-difluoroethylene moiety as a bioisostere has been in the design of improved derivatives of the antimalarial agent artemisinin (346) for which resistance is beginning to emerge.(154,155) The difluorinated alkene 347 was conceived as a more stable derivative of the lactone in 346, with in vitro potency improved 2-fold compared to the progenitor.(154) Intraperitoneal (IP) administration of 347 to mice infected with Plasmodium berghei at a dose of 35.5 μmol/kg for 4 days resulted in no detectable parasitemia on day 4 compared to parasitemia levels of 25% for animals dosed with 346 and 50% for the untreated control group.(154b) In this setting, a CF3-alkene moiety is also an effective carbonyl bioisostere, as demonstrated by the potent in vitro antimalarial activity associated with 348.(154a)

The CF2 Moiety as a C═O Bioisostere

A CF2 moiety has been shown to function as an effective ketone bioisostere when installed in analogues of nonimmunosuppressive inhibitors of FK506-binding proteins (FKBPs), members of the immunophilin class of chaperones.(156) The in vitro and in vivo neurotrophic activity exhibited by the immunophilin FK506 (tacrolimus, 349) can be recapitulated by nonimmunosuppressive compounds that mimic the FKBP12-binding portion of the macrolide lactone. The design concept explored initially assessed replacing the ketone carbonyl of the prototype molecule 350 with a CF2 to afford 351, a compound that performed slightly better as an inhibitor of FKBP12 rotamase activity than the progenitor. The importance of the CF2 element was underscored by the absence of significant rotamase inhibition by the CH2 homologue 352. Chemical stability studies indicated that 351 was stable over 27 h in phosphate-buffered saline/DMSO, alleviating concerns around the benzylic difluoride moiety and particularly its relationship with the electron rich aromatic ring. The optimized molecule 354, which was patterned as an analogue of V-10367 (353), inhibited FKBP12 rotamase activity with a Ki of 19 nM, potency that compared favorably with the 0.3 nM Ki observed for 353 under comparable experimental conditions.(156) An X-ray cocrystal structure of 354 bound to FKB12 indicated that one of the fluorine atoms was close to the hydrogen of Tyr26–OH (F to O distance = 3.18 Å), resembling the H-bonding interaction of the ketone C═O of 353, while the second fluorine atom interacted with a meta hydrogen of Phe36 with an aromatic carbon to fluorine distance of 3.02 Å.(156a)
The pyrazolo[4,3-c]pyridine 355 was characterized as a potent γ-secretase inhibitor that was active in vivo in a wild-type FVB mouse model, reducing brain Aβ40 levels by 25% following an oral dose of 5 mg/kg despite the low oral bioavailability (2.5%) of this compound.(157) However, 355 was labile in liver microsomes, with oxidation of both the ethyl substituents and the methylene that is exocyclic to the pyrazole identified as significant sites of metabolic susceptibility. In addition, the pyrazole ring N atom was subject to rapid glucuronidation, while GSH adducts were formed by a process that involved the direct displacement of the chlorine substituent on the phenyl ring.(157) Iterative optimization to address these problems led to the identification of the ketone analogue 356, which was less susceptible to glucuronidation but exhibited poor biological activity in a cell-based assay, despite potent intrinsic enzyme inhibition. This was traced to a chemical degradation pathway that involved elimination of 4-chlorophenylsulfinic acid from these molecules to afford the corresponding hydroxy pyridines 357. Replacing the ketone C═O with a CF2 gave a series of compounds from which 358 emerged after further structural manipulation designed to more comprehensively address HLM instability. This compound lowered brain Aβ40 by 27% in vivo in a mouse model following oral administration of a dose of 1 mg/kg.(157)
In a series of atypical antipsychotics where the combination of antagonist activity at the dopamine D2 and serotonin 5HT2A receptors with agonist effects at the serotonin 5HT1A receptor was sought, the CF2 moiety in 360 performed similarly to the ketone 359, an SAR point reproduced in analogues in which the benzothiophene moiety was varied.(158,159)

Fluorinated Motifs as Amide, Sulfonamide, and Urea Mimetics

ARTICLE SECTIONS
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Trifluoroethylamine and Difluoroethylamine Derivatives

The bioisosteric relationship between a trifluoroethylamine moiety and an amide functionality was originally conceived by Zanda who examined its potential in the context of designing peptidomimetics (Figure 26).(159,160) In addition, the plasticity of this structural element was recognized based on its potential to be incorporated either in register within the peptide frame, as depicted in Figure 26B, or in the partially retro-inverted configuration illustrated in Figure 26C.

Figure 26

Figure 26. Incorporation of the CF3CH2NH motif in a polypeptide backbone in register (B) or in a partially retro-inverted configuration (C) that mimics the amide of a conventional polypeptide (A).

The fundamental basis for mimicry between the CF3CH2NH moiety and the more recently explored CHF2CH2NH homologue and an amide is captured in Figure 27 and relies upon both geometrical and electronic considerations.(159) The key C–C–N bond angle of the CF3CH2NHR moiety is comparable to that of an amide, while the electron withdrawing effects of the CF3 moiety reduce the basicity of the amine such that the H-bond donating properties of the N–H are more like that of an amide N–H.(159) In addition, the C–F dipoles and electron density are believed to provide some emulation of the amide oxygen lone pairs of electrons. Somewhat analogously, the RCF2CH2NH may be viewed as a sulfonamide mimic in which the two fluorine atoms function as metaphors of the sulfone oxygen atoms, with the imprecise topographical relationships between the bonds of the two moieties possibly compensated by the longer C–S and N–S bonds.(159c) These structural elements have the advantage of relieving the topographical constraints imposed by an amide functionality which, in appropriate circumstances, may enhance complementarity with a specific target. While deployment of the CF3CH2NH or CHF2CH2NH moieties eliminates metabolic sensitivity to amidases, esterases, and proteases, these motifs do introduce a new asymmetric center.

Figure 27

Figure 27. Functional aspects of the mimicry between an amide and a sulfonamide moiety and CF3CH2NH and CHF2CH2NH.

The CF3CH2NH moiety has found application as an amide bioisostere beyond incorporation into peptidomimetics, most prominently in mechanism-based inhibitors of the cathepsin family of cysteine protease inhibitors from which the cathepsin K inhibitor odanacatib (361) was derived.(161) An analysis of the X-ray cocrystal structures of peptide-based inhibitors of cathepsin K revealed that while the P1–P2 amide engaged the protein via H-bonding interactions involving both the N–H and C═O oxygen atom, the P2–P3 amide element relied upon a H-bond interaction involving only the N–H as a donor.(161a) This inspired the design of trifluoroethylamine derivatives that would reduce the pKa of the amine while preserving the H-bond donor attributes. The data presented for 362365 in Table 30 provides key insights into the identification of suitable amide bioisosteres in this series.(161b) The compiled SARs indicate the importance of amine pKa because the CH3 analogue 364 is 1000-fold less potent than the CF3 derivative 362; however, the CF3CF2 homologue 363 is somewhat less potent, while the nitrile 365, which has the lowest pKa within this series, is 30-fold weaker than 362. These results focused attention on the trifluoroethylamine series which was elaborated into the exquisitely potent inhibitor 366, IC50 = 5 pM, a compound that identified the preferred absolute configuration at the trifluoroethylamine asymmetric center because the epimer 367 is almost 1000-fold less potent, IC50 = 4.6 nM.(161) However, the basicity associated with the piperazine moiety of 366 led to its accumulation in acidic lysosomes, rising to concentrations where it was able to inhibit cathepsins B, L, and S despite lower intrinsic inhibitory activity toward these proteases, IC50 values of 111, 47, and 451 nM, respectively. Consequently, the next phase of iterative compound design focused on structural modifications that avoided overt basicity, accomplished initially with the discovery of 368, cathepsin K IC50 = 0.2 nM, that was cocrystallized with the enzyme.(161) The X-ray data confirmed effective amide emulation, with the trifluoroethylamine N–H engaging the carbonyl oxygen atom of Gly66, while the CF3 moiety projected into bulk solvent. The structural data also confirmed mechanism-based inhibition, with the nitrile moiety of 368 engaging the catalytic cysteine as a covalent iminothioether (Pinner-type) adduct. Further optimization of 368 focused on modulating the PK profile, with the sulfonamide replaced by a methylsulfone and a fluorine introduced to the isoleucine methine carbon atom to block a site of metabolic hydroxylation. A cyclopropyl moiety at P1 was installed to reduce susceptibility of the amide toward hydrolysis resulting in 361, a potent cathepsin K inhibitor, IC50 = 0.2 nM, that exhibited good selectivity for this enzyme over cathepsins B (IC50 = 1034 nM), L (IC50 = 2295 nM) and S (IC50 = 60 nM).(161c) Although 361 completed advanced clinical trials as a potential treatment for osteoporosis and bone metastasis, increasing bone mineral density and reducing the risk of fractures in patients, the compound was abandoned by its sponsor prior to the filing of an NDA due to the observation of an increased risk for cardiovascular events associated with drug therapy.(161d)
Table 30. SARs Associated with the Series of Cathepsin K Inhibitors 362365 that Incorporate Potential Amide Bioisosteres at the P2–P3 Junction
 Rcathepsin K IC50 (nM)pKa
362CF30.91.3
363CF2CF32.41.8
364CH39886.7
365CN300.7
The high crystallinity associated with 361 resulted in low aqueous solubility, a property that contributed to the low (≤10%) oral bioavailability observed after administration of the drug as a suspension to preclinical species.(162) In an effort to address the dissolution-limited bioavailability, the difluoroethylamine analogue 369 was prepared with the anticipation that the enhanced basicity (pKa increased by ∼1 unit) would facilitate salt formation with sulfonic acids and HCl and lead to reduced lipophilicity, with Log D decreased from 3.53 for 361 to 0.11 for 369. Compound 369 retained the potent cathepsin K inhibitory activity (IC50 = 1 nM) and protease selectivity associated with 361, while the modified physicochemical properties led to improved oral bioavailability in rats when the compound was administered as a 1% methocel suspension.(162)
A trifluoroethylamine moiety was examined as an amide bioisostere in the design of inhibitors of BACE-1, where a replacement for the anilide in 370 was sought to alleviate concerns about release of the aniline in vivo and its potential to express toxicity after metabolic activation.(164) The drug design process specifically focused on preserving the N–H of the anilide moiety of 370 because this was involved in a critical H-bonding interaction with the C═O oxygen of Gly230 of the enzyme based on an X-ray cocrystal structure of a related analogue. It was recognized that the conformational constraint imposed by the planar anilide might be optimized for interaction with Gly230 by a benzylamine moiety because it was anticipated to adopt an orthogonal arrangement with respect to the plane of the fluorophenyl ring. Initial derivatization took advantage of a reductive amination protocol to prepare libraries which identified the ethylamine 371 as a modest inhibitor of BACE-1 in a cell-free biochemical assay, IC50 = 13.9 μM. However, 371 was considerably more potent in the cell-based screen, which was attributed to concentration of the basic drug in the acidic endosomal compartment where BACE-1 is located. Consequently, further modification focused on modulation of amine basicity, which was accomplished by fluorination (372377), as summarized in Table 31. The CF3-cyclopropane moiety in 377 provided the optimal balance of properties, although further structural manipulation of this chemotype was required in order to surmount a problem associated with problematic CYP 2D6 inhibition. The conformational changes anticipated in the design phase were observed in an X-ray cocrystal structure of 377 with the BACE-1 enzyme, although the compound bound slightly differently in the active site compared to 370 in order to accommodate the altered drug–target vectors. The CF3 substituent projected into the vestibule of the S3 pocket, while the cyclopropyl ring filled a lipophilic pocket at the rear of the interface of the S1 and S3 pockets. This application provides an illustrative example of the advantage of the CF3CH2NH as an amide bioisostere where relief of steric constraint is beneficial.(163)
Table 31. SARs Associated with the BACE-1 Inhibitors 371377a
a

*WCA = whole cell assay.

RCF2CH2NHR′ as a Bioisostere of RSO2NHR′

While a bioisosteric relationship between the sulfonamide and RCF2CH2NH moieties has not been explicitly recognized, inhibitors of the serine protease thrombin provide an example of the potential for this kind of structural metaphor.(139,159c) The X-ray cocrystal structures of thrombin and factor VIIa inhibitors (Figure 21) indicate that the anilide N–Hs of 378 and its analogues 379382 engage with the backbone C═O oxygen atom of Gly216 in a H-bonding interaction; however, 378 is a modestly potent inhibitor of thrombin with a Ki value of 1.28 μM (Table 32). The difluoroethylamine 379 is 27-fold more potent, while the pyridine analogue 380 adds a further 6-fold potency increase. In this example, fluorination is of importance because the dimethyl and cyclopropyl derivatives 381 and 382, respectively, are several fold less potent.(139a) Interestingly, the fluorine atoms were originally introduced as a means of abrogating metabolic modification at the benzylic site rather than for the purpose of structural emulation.(139d)
Table 32. Structure–Activity Relationships for the Thrombin Inhibitors 378382
Comparison of the thrombin inhibitory effects expressed by 383 and 384 illustrates a broad-based application of biosisosterism in drug design.(138,139) In these molecules, the oxyguanidine provides a mimetic of the guanidine found in natural substrates but with reduced basicity to facilitate oral delivery, the fluorobenzene ring of 383 can be viewed as a bioisostere of the cyclic amide of 384 while the difluoroethylamine of 383 functions analogously to the sulfonamide of 384.

Fluorinated Amines and Mimesis of Imide-like Motifs

The N-(2,2,2-trifluoroethyl)methanesulfonamide moiety has found application in the optimization of HCV NS4B and acyl-CoA:monoacylglycerol acyltransferase (MGAT) inhibitors.(164,165) Symmetrical monofluorination of each of the CH3 groups of 385 enhanced potency 3-fold (386), but N-dealkylative metabolism gave difluoroacetone, a compound associated with significant toxicity, while glutathione adducts resulted from oxidative metabolism of the indole heterocycle (Table 33).(164a,b) Pefluorination of a single CH3 moiety of 385 gave a pair of enantiomers, of which the (S)-isomer 387 was 30-fold more potent than the (R)-isomer 388, while the homologues 389 and 390 were less potent. Further optimization gave 391 as a compound that was advanced into clinical trials.(164c)
Table 33. Structure–activity Relationships Associated with HCV NS4B Inhibitors
The MGAT inhibitor 392 was claimed to express an IC50 value of <12 nM in a biochemical assay and inhibit MGAT expressed in a Caco-2 cell line with an EC50 value of 58 nM, biological effects that translated to a 69% reduction in triacylglycerol absorption in male beagle dogs after an oral dose of 30 mg/kg.(165)
There are several higher homologues of the CF3CH2NH moiety that appear to offer opportunity for evaluation as potentially interesting structural metaphors. However, while these have not been the subject of systematic analysis in the context of bioisosteric relationships or the delineation of key physicochemical properties, there are examples of applications scattered throughout the literature in molecules that, in some cases, have been studied in some detail in a preclinical setting. In this section, I highlight representative examples that demonstrate applications in drug design, and which, if applied in an informed fashion in the appropriate context, may offer interesting benefits.
Inhibition of steroid 5α-reductase enzymatic activity has been shown to be sensitive to amide substitution patterns in a series of azasteroid-based inhibitors, particularly with respect to influencing activity toward the type I enzyme that is only modestly inhibited by 18.(166) The introduction of the phenyl ring in dutasteride (393) is associated with potent type I 5α-reductase inhibition that affords a more balanced 5α-reductase inhibitor than 18 (Table 34). The benzylamine derivative 394 exhibits enhanced potency toward the type 1 enzyme compared to 18, which is further enhanced by replacement of the CH3 with a second CF3 moiety, as depicted by 395.(167) This modification removes the chirality associated with 394 and would be expected to enhance the H-bond donating capacity of the amide N–H, although in this example the N–H does not appear to be specifically involved in drug–target interactions.(168)
Table 34. Inhibition of Steroid 5α-Reductase Enzyme Activity by Aza Steroid Derivatives 18 and 393395
 steroid 5α-reductase enzyme inhibition IC50 (nM)
 rat prostatehuman prostatehuman type Ihuman type II
1830/3252/58470/313a8.5/11.3a
393  4b<0.1b
3941516363.3
39534203.91.8
a

Data taken from 2 independent assays abstracted from different articles.(166,167)

b

Under the assay conditions used to generate this data, finasteride inhibited the type I and type II enzymes with IC50 values of 150 and 0.18 nM, respectively.(166)

N-CH(CF3)2 as a Sulfone Bioisostere

Diarylsulfonylureas, of which sulofenur (396) is the representative prototype, were discovered as cytotoxic antitumor agents using an in vivo screen conducted in mice implanted subcutaneously with solid tumors, a screening approach developed as an alternative to the more traditional approach of in vitro evaluation using hematopoietic tumor-derived cell lines.(169) Clinical toxicity associated with the metabolic release of 4-chloraniline from 396 led to its replacement by LY295501 (397).(170,171) The mode of antitumor action of the sulfonyl ureas is enigmatic but has been attributed, in part, to mitochondrial uncoupling.(170,172) The discovery of 396 stimulated considerable interest in this class of antitumor agent, and one interesting class of cytotoxic agent is provided by 398400.(173) The mode of action of 398400 is equally enigmatic, but one interpretation is that they may be related to the sulfonylureas in a fashion that relies upon a bioisosteric relationship between the (CF3)2CH and SO2 moieties. Unfortunately, MMPs are not available that would allow a more precise comparison. However, that the electron withdrawing effects of the two CF3 substituents influence the proximal urea moiety was indicated by the presence of the isourea tautomer that was observed in polar solvent by 1H NMR spectroscopic analysis.(173a)

Fluorinated Motifs and Urea Bioisosterism

A careful and detailed theoretical analysis of the isosteric relationship between the urea 401 and fluoro enamide 402 has been conducted that recognizes the close topological similarities depicted in Figure 28.(174) However, while the bond angles and lengths show a close and compelling analogy, only N-alkyl, N-tosyl derivatives were prepared as part of the survey, and although these were shown to be chemically stable under neutral, basic, and acidic conditions, the synthesis of compounds with a free N–H was not described. In addition, there was no discussion of the pKa value of the N–H in 402 and its homologues. Nevertheless, this motif represents an interesting element for use in drug design, particularly for analogues of ureas that do not possess a free N–H and would thus be more amide-like. However, this moiety has not been adequately explored despite its potential to also be considered as an amide bioisostere, with functional mimicry potentially extending to the CF3 and CF2H derivatives 403405, respectively.

Figure 28

Figure 28. Bond angles and lengths that illustrate topological mimesis between a urea and a fluoroenamide.

In a series of dopamine D2 partial agonists explored for their potential to treat schizophrenia, the N–H of benzimidazolone of 406 that is distal to the oxyethylamine side chain functioned as a phenol bioisostere.(175) The cyclic urea motif of 406 was effectively mimicked by the 2-trifluoromethyl-substituted benzimidazole 409, which was 24-fold more potent than the methyl homologue 408 and 54-fold more potent than 407, the parent molecule of this series, presumably a reflection on the H-bond donating properties.(175c) Further optimization focused on fused pyran derivatives designed to confer conformational restraint, with both 410 and 411 potent ligands for the high affinity dopamine D2 receptor.(175a,d) However, in this chemotype, the 2-trifluoromethyl-substituted benzimidazole was a less effective mimic of the urea of 410 and amide of 411, with 15–40-fold lower affinity, for which speculation focused on an effect of ring fusion on the preferred tautomeric state of 412.(175d)

Fluoroamides and Urea Bioisosterism

α-Fluoromethyl and α,α-difluoromethyl secondary amides preferentially adopt a conformation in which the C–F and C═O bonds are aligned in a trans-relationship that is favored by both dipole interactions and reinforced by an electrostatic interaction between the fluorine atom and the amide N–H (Figure 29).(176−178) Indeed, this phenomenon has been exploited to illuminate the topography of the vanilloid receptor (TRPV1) agonist activity of capsaicin (413) by synthesizing and evaluating the α-fluorinated enantiomers 414 and 415.(179) The similar performance of 414 and 415 as agonists at the TRPV1 receptor led to the conclusion that the bound form was the extended conformation depicted in Figure 30A that is accessible to both enantiomers rather than the alternative topography presented in Figure 30B.(179)

Figure 29

Figure 29. Calculated conformational preferences for α-fluoromethyl and α,α-difluoromethyl secondary amides.

Figure 30

Figure 30. Conformational preferences of the α-fluorinated enantiomers of 413 designed to illuminate the bound conformation.

However, there are circumstances where this inherent preference can be overridden in favor of the gauche conformation, which for a simple α-fluoromethyl amide has been calculated to be ∼6 kcal/mol higher in energy than the trans conformer, while for the α,α-difluoromethyl homologue the energy of the conformation that places the C–H and N–H in a syn relationship is ∼4.5 kcal/mol higher (Figure 31).(180) Under these circumstances, α-fluoromethylamides and, particularly, α,α-difluoromethylamides, offer an opportunity to function as urea mimetics, as illustrated by the solid state structure of 416 which crystallizes in the conformation shown, stabilized by close contacts between both the N–H and C–H hydrogen atoms and the pendent carbamate oxygen atom. The bistrifluoromethylamide 417 and monotrifluoromethylamide 418 behave in a similar fashion, with the C–H to oxygen H-bond in 418 shorter than that in 417, reflecting the poorer H-bond donor effects of this motif, anticipated based on the differences in electron withdrawing effects and polarizability.(180a) These molecules adopt conformations comparable to that observed with the thiourea 419, and fluorinated acetanilides have been exploited with some success as organocatalysts based on the anticipation that they would recapitulate the effects of ureas and urea mimics.(180,181) However, the α-fluoro derivatives are more active catalysts than the α,α-difluoro analogues, perhaps surprising based on the calculated H-bond strengths which have been estimated to be ∼3.0 kcal/mol for the α-fluoro derivatives and ∼4.0 kcal/mol for the bis-CF3 amides, with the latter more capable of overcoming the natural bias toward a conformation in which the F and amide and C═O are in a trans-periplanar arrangement.(181)

Figure 31

Figure 31. Topologies and bond lengths associated with α-fluoro-substituted amides 416418 and urea 419 in the solid state.

These motifs have found only very limited application in drug design presumably a function, in part, of concern for the release of difluoroacetic acid and fluoroacetic acid in vivo. However, an interesting example where the fluorination pattern of an amide moiety exerted an effect on ligand–protein interactions is provided by the disaccharide derivatives 420423 which bind to the lectin wheat germ agglutinin (WGA), although in this example urea isosterism is not a basis.(182) The mono- and difluoro-acetamides 421 and 422, respectively, bind more tightly to WGA based on NMR analyses than the acetamide 420 and, particularly, the trifluoroacetamide 423. These data were interpreted in the context of a productive C–H to π interaction between a C–H of the acetamide moiety and the phenol ring of a tyrosine residue of WGA. The electron withdrawing effects of fluorine substitution in 421 and particularly 422 polarize the C–H bond, thereby enhancing this interaction. The importance of the effect is underscored by 423, which cannot engage in this kind of interaction and exhibits an order of magnitude lower affinity for WGA than 422.(182)
Halogenated amide analogues of melatonin (424) and agomelatine (426) have revealed interesting structure–activity relationships that indicate the importance of the fluorination pattern on binding affinity (Table 35).(183) The CF3 amide 429 derived from 426 shows reduced affinity but similar receptor selectivity, while the CH2F homologue 427 exhibits 10-fold selectivity for the MT2 receptor subtype. In contrast, the CHF2 amide is 10-fold selective for MT1 receptor and retains the potency of 426, a profile analogous to that of the urea 431, while the balanced profile and reduced potency of the CHCl2 amide 430 illustrates the importance of selecting the correct halogen.(183)
Table 35. Structure–Activity Relationships Associated with Melatonin Agonists
 MT1 (pKi)MT2 (pKi)
4249.349.02
4259.7a 
426∼10∼10
4278.219.40
42810.279.07
4298.248.75
4308.308.75
43114.37.62
a

Data from an assay assessing binding to cell membranes using ligands that do not distinguish the receptor subtypes(183a)

C–F as a Carbinol (C–OH) Mimic

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C–F as a C–OH Bioisostere in Nucleoside Analogues

Replacing the hydroxyl substituents and hydrogen atoms of the ribose ring of nucleosides with fluorine has been extensively explored, with gemcitabine (432), the HBV inhibitor clevudine (433), and the HCV inhibitor sofosbuvir (434), a phosphoramidate prodrug, the most prominent clinically approved fluorinated nucleoside derivatives.(184−187) The introduction of fluorine atoms to the ribose ring has a complex influence on the shape of a nucleoside analogue, with antiperiplanar effects, dipole–dipole, anomeric, and gauche interactions contributing to the overall conformational bias, while interactions between fluorine atoms and a pendent C–H of the ribose or the base can also play a role. Consequently, the outcome is dependent upon the specific topological arrangement of functionality and their stereochemical relationships, with complexity heightened by the potentially selective effect on recognition by kinases and viral polymerases. For example, a 2′-α-fluoro substituent in a 3′-deoxy ribose favors a north conformation of the ribose ring while 2′-β-fluoro substitution prefers the south conformation but less strongly, although this preference can be reinforced by a 3′-α-fluoro substituent (Figure 32). Because HIV-1 reverse transcriptase is believed to recognize nucleotides adopting the south conformation, 2′-α-fluoro substitution leads to inactive antiretroviral agents.(188) This contrasts with the effect of 2′-β-fluoro-substitution on ribose topography, which has been shown to preferentially adopt the south conformation.(189)

Figure 32

Figure 32. Preferred conformation of a 2′-α-fluoro-substituted ribose compared with a 2′-β-fluoro substituted isomer and a 2′-β, 2′-α-difluoro-substituted ribose ring.

The importance of the correct fluorination patterning is most effectively illustrated by the poor HCV inhibitory activity associated with 435, the 2′-β-fluoro analogue of 434.(190) The 2′-fluorine atom of 434 mimics the effects of the 2′-hydroxyl of 436, while 435 mimics that of 437. While conformational preferences may contribute to these observations, specific interactions with the HCV NS5B polymerase also play a role because it is sensitive to the identity of the 2′-α- and 2′-β-substituents, critical ribose recognition elements for Ser282 of the enzyme.(187b) While the fluoride of 434 lacks the H-bond donating properties of the hydroxyl of 436 (Figure 33A) and binding leads to a disturbance in the interaction network associated with the 2′-hydoxyl, it appears to be capable of interacting with a side chain N–H of Asn291 (Figure 33B), and although the Km is higher, this nucleotide is able to align correctly for incorporation into the growing RNA chain.(187b)

Figure 33

Figure 33. Key H-bonding interactions between a 2′-methyl ribose moiety (436) and the 2′-fluoro-2′-methyl homologue that is the ribose hallmark of 434.

However, there are limits to the bioisosteric relationship between a 2′-fluoro and a 2′-hydroxyl substituent in the context of RNA. While the use of fluorinated RNA is common in siRNA and aptamers as a means of stabilizing the RNA, incorporation into RNA:DNA hybrids has been found to be poorly efficacious toward activating mammalian RNaseH.(191)
Collagen is the most abundant protein in animals, amounting to ∼30% of the total protein content of humans and ∼75% of the weight of human skin. The polypeptide chains of collagen are comprised of approximately 300 repeats of the triplet sequence XYG in which X is often an l-Pro residue while Y is frequently a 4-(R)-hydroxy-l-proline (438, Hyp) residue.(192) These sequences contribute to both the structure and stability of collagen chains, which adopt tightly wound triple helices that are organized into fibrils conferred with considerable tensile strength. The hydroxyl moiety of Hyp is known to contribute to the properties and stability of collagen but its precise function has been esoteric in nature, initially attributed to either its H-bonding properties or an effect on stabilizing trans-peptide bonds along the backbone. However, studies with 4-fluoroproline (439) as a bioisosteric substitute for the Hyp residue 438 indicate that the predominant effect of 4-substition is to influence the conformation of the pyrrolidine ring of proline, with both the 4-(R)-hydroxy and 4-(R)-fluoro substituents favoring a Cγ-exo conformer as depicted in Figures 5B.(192)
The antibiotic pristinamycin IIB (440), which incorporates d-proline and inhibits protein synthesis by acting on bacterial ribosomes, suffers from dehydration at acidic and basic pH to give a conjugated trienone, which is inactive as an antibacterial agent.(193) To identify structural modifications that would address this problem, reduction of the ketone to an alcohol was explored, with the result that both inhibition in a cell-free translational assay and antibacterial activity were preserved with the (R)-isomer 441 (Table 36). In contrast, the (S)-alcohol 442 was 120-fold less potent in the cell free translation assay and 8-fold less potent as an antibacterial agent. These structure–activity observations were recapitulated with the (R)- and (S)-fluorides 443 and 444, respectively, with the former exhibiting potency similar to 441, while 444 was 10-fold more potent than 442 in the protein translation assay and 4-fold improved in the antibacterial assay.(193)
Table 36. SARs Associated with 440 and Its Analogues
 Rpoly(U) IC50 (μM)MIC (IP8203) (μg/mL)
440C═O0.14
441(R)-CHOH0.051
442(S)-CHOH632
443(R)-CHF0.060.25
444(S)-CHF0.58

Fluorinated Motifs and Alcohol/Thiol Bioisosterism

Fluorine has played a role in the design of bioisosteres of alcohols and thiols where the CHF2 moiety has been exploited as a H-bond donor while replacing a C–OH with a C–F relies upon the ramifications of dipole mimicry.
The intramolecular interaction between the CHF2 moiety of the pyrazole-based fungicide 445 and the adjacent C═O has been characterized as H-bonding in nature based on IR and 1H NMR data.(194) The energy of the intramolecular interaction in 445 has been estimated to be ∼1.0 kcal/mol based on a distance of 2.4 Å, which calibrates the CHF2 moiety as a relatively weak H-bond donor compared to more traditional functionalities which are typically associated with energies of 2–15 kcal/mol. Nevertheless, this interaction appears to be important to the fungicidal activity of 445, which is a consequence of inhibiting fungal succinate dehydrogenase because the CF3 homologue, which is absent the H-bond donor, exhibits weaker biological effects.(194,195) The 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide moiety is a common structural element in a range of fungicides, including fluxapyroxad (446), sedexane (447), and isopyrazam (448).(195) More recently, intermolecular H-bonds have been observed between the CHF2 moiety and the nitrile of an adjacent molecule in the single-crystal X-ray structure of the oxadiazole derivative 449, with the key bond angle and length captured in Figure 34.(196)

Figure 34

Figure 34. Intermolecular H-bond observed in the single-crystal X-ray structure of oxadiazole 449.

Perhaps the most compelling application of the CHF2 moiety as a H-bond donor is provided by 452, an inhibitor of HCV NS3 protease in which the difluoro-Abu was designed as a mimic of the cysteine residue found at the P1 site of natural substrates, with the structural similarity illustrated in simplistic fashion in Figure 35.(197a) The design of this compound was inspired by the earlier observations with the pyrazole 445, and 452 was found to be equipotent with the Cys analogue 450, indicative of good functional emulation. Satisfactory bioisosterism was further emphasized by the 20-fold reduced potency observed with the Ala analogue 451, reflecting the importance of the presence of the H-bond donor in 452.

Figure 35

Figure 35. Illustration of the functional mimicry between RSH and RCF2H in P1 residues incorporated into 450 and 452.

The presence of an intermolecular interaction between the CHF2 moiety and the HCV NS3 protein was confirmed with X-ray cocrystal structures of the smaller inhibitors 453 and 454, both of which formed a mimic of the tetrahedral reaction intermediate by the addition of the catalytic Ser139 hydroxyl to the activated carbonyl moiety that is a hallmark of these compounds.(197b) The X-ray structures indicated that the hydrogen atom of the CF2H element donated a H-bond to the backbone C═O of Lys136, while one fluorine atom was close to the C-4 hydrogen atom of the phenyl ring of Phe154, suggestive of a weak C–H to fluorine H-bonding interaction. The H-bond lengths measured for the CF2H moiety were ∼2.57 and ∼2.9 Å, at the upper end of the preferred distance but consistent with the 2.9 Å suggested for C–H to oxygen interactions with aromatic ring donors.(139c,197b)
However, in the X-ray cocrystal structure of the related α-keto acid 455 bound to HCV NS3, the carbon atom of the CHF2 was found to be 6.28 Å away from the backbone C═O of Lys136 and 4.08 Å away from the backbone C═O oxygen atom of Leu135.(197c) The 4.08 Å distance represents a C–H to OH-bond that is probably above the preferred limit, so while not ideal, it was nevertheless considered to play a role in drug–target interactions.(139,198) These observations reflect significant differences between this complex and those obtained with 453 and 454 because with 455, the serine hydroxyl approached the activated C═O from the opposite face to that typically observed with serine proteases. This arrangement resulted in the carboxylate moiety rather than the hemiketal oxygen atom occupying the oxyanion hole. The difluoromethyl side chain fitted snugly into the S1 pocket with one of the fluorine atoms proximal (3.34 Å) to the C-4 hydrogen atom of the thiophene ring, viewed as a form of hydrophobic collapse that may preorient the molecule for presentation to the protease in its extended conformation.
The direct translation of this Cys mimic to the P1 element of tripeptide-based inhibitors derived from asunaprevir (456) was unsuccessful, with the naturally configured 457 found to be 900-fold less potent in the GT-1a enzyme assay than 456, while the unnatural isomer 458 was a further 2-fold weaker and demonstrated poor inhibition in the GT-1b replicon (Table 37).(199) This SAR point was mirrored by the des-fluoro derivatives 459 and 460, which were poor enzyme inhibitors, observations that demonstrated the importance of the cyclopropane moiety at P1 of 456. However, replacing the vinyl substituent of 456 with a CHF2 afforded the potent inhibitor 461, with activity dependent on configuration because 462 was an order of magnitude weaker in the enzyme assay. The unique attributes of the CHF2 substituent in this setting were underscored by the 10-fold loss in potency observed with the des-fluoro derivative 463 and the fully fluorinated homologue 464, while projecting the CHF2 moiety further from the core, as in 465, also led to reduced potency. In this analogue, the presence of the fluorine atoms incurred a small but negative impact compared to the simple ethyl derivative 466. An X-ray cocrystal structure of 451 with HCV NS3 protease revealed a close approximation of the hydrogen atom of the CF2H moiety to the backbone carbonyl of Leu155 at a distance that was consistent with a H-bonding interaction.(199)
Table 37. SARs Associated with the HCV NS3 Protease Inhibitors 456466
The importance of the CHF2-substituted cyclopropyl moiety identified with 461 in HCV NS3 protease inhibitor design is reflected in the incorporation of this structural element in the potent inhibitors glecaprevir (467) and voxilaprevir (468), both of which express pan-genotypic activity and each of which has been approved for marketing by the FDA as part of a drug combination regimen.(200,201)
Lysophosphatidic acid (LPA) 469 interacts with four GPCR receptors designated as LPA1–4 and also acts as an agonist for the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ). However, the propensity of LPA to rearrange by acyl migration inspired the design of the difluorinated LPA analogue 470 in which the terminal primary alcohol has been replaced by a difluoromethyl moiety.(202) While 470 failed to interact with LPA1–3 receptors, this compound stimulated the PPARγ receptor as detected by luciferase expression in CV-1 cells transfected with the enzyme under control of a PPARγ-responsive element, demonstrating the contextual nature of bioisosterism and the limits of functional mimicry.
The bioisosteric relationship between the CHCF2 and OH moieties has been extended to hydroxamic acids where incorporation of an N–CHCF2 element functioned as an effective mimic in the context of the 5-lipoxygenase inhibitors 471 and 472.(203)

CF2 as a Bioisostere of an Oxygen Atom

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CF2 and Phosphate/Pyrophosphate Mimicry

The CF2 moiety has been explored extensively as a mimic of an oxygen atom in a variety of structural backgrounds in which the C–F bond is considered to be a mimic of the one of the lone pairs of electrons of oxygen. A seminal example is provided by studies of phosphate chemistry where a phosphonate is frequently employed as a bioisostere. However, this substitution leads to lower acidity compared to a phosphate, which can result in poor functional emulation (Tables 38 and 39). The data compiled in Table 37 illustrates the significant differences between the acid dissociation constants for pyrophosphate (473) and the CH2 analogue 474.(204,205) While the CCl2 homologue 475 reduces the pKa values compared to 474, fluorination offers a superior effect, with the CF2 derivative 476 the optimal mimic with respect to reproducing the acidity of 473. Indeed, the electron withdrawing properties of fluorine are such that, in this context, monofluoro substitution (474) is as effective at modulating the acidity as two chlorine atoms.
Table 38. pKa Data for Pyrophosphate (473) and Its Carbon Analogues 474478
 473474475476477478
XOCH2CCl2CF2CHFC(OH)2
pKa22.362.87 <2.6<2.7 
pKa35.777.456.115.806.155.81
pKa48.2210.969.788.009.358.42
Table 39. pKa2 Values for a Homologous Series of Phosphonic Acid Derivatives Compared to the Phosphate Phenyl Ester
 PhOP(O)(OH)2PhCH2P(O)(OH)2PhCH(F)P(O)(OH)2PhCF2P(O)(OH)2
pKa26.227.726.605.71
The recognition that the physical properties, bond angles, and bond lengths of difluoromethylenephosphonate render it an effective mimic of phosphate has led to its widespread adoption in the design of inhibitors of phosphatases that are of physiological relevance (Figure 36).(206−208) The synthesis of 479 as a building block for the construction of nonhydrolyzable tyrosine phosphate mimics for use in the design of phosphatase inhibitors was followed by the development of 480 as a mimic of phosphorylated serine, motifs that have been extended to sphingomyelin and other naturally occurring phosphate elements.(209−211)

Figure 36

Figure 36. Geometric parameters for the phosphate, phosphonate, and difluoromethylenephosphonate moieties.

The difluoromethylenephosphonate 481 inhibited PTP1B with an IC50 value of 120 nM, was active in a cell-based assay with an EC50 = 1.2 μM, and exhibited 13% oral bioavailability in the rat, with a Cmax of 35 μM, plasma exposure that reduced glucose levels in rat and mouse models after single oral doses of 30 and 10 mg/kg, respectively.(212) The furan carboxylate of 482 was introduced to engage a H2O molecule observed in the active site of Yersinia pestis outer protein H (YopH) phosphatase, and this compound was a potent inhibitor, IC50 = 190 nM, that reduced intracellular Yersinia pestis replication by 9-fold at 10 μM, a concentration below that where cytotoxicity was seen.(213) The phosphopeptidomimetic 483 targeted the Src homology 2 (SH2) domain of signal transducer and activator of transcription 6 (STAT6) and blocked phosphorylation of Tyr641 of STAT6 in intact Beas-2B cells when introduced as its bis-pivaloyloxymethyl prodrug at concentrations of 1–10 μM.(214)
The difluoromethylenephosphonate 485 was designed as an analogue of sphingomyelin (484) that inhibited Bacillus cereus sphingomyelinase with an IC50 value of 57 μM, 2-fold more potent than the des-fluoro analogue.(215)

CF2 as an Oxygen Bioisostere in Sulfonic Acids and Sulfonamides

The effects of fluorination α- to sulfonic acids and sulfonamides has been examined in the context of inhibition of steroid sulfatases, protein phosphatases, and carbonic anhydrase.(216−220) Steroid sulfatase (STS) catalyzes the hydrolytic desulfation of steroid-based sulfate derivatives to afford the free phenols. Estrogen sulfate (486) and estrone sulfate (487) are substrates for STS, and the former is believed to act as a reservoir for the production of estrogen in breast tumors, suggesting this enzyme as a potential therapeutic target.(217) Sulfonates have been evaluated as STS inhibitors but were poorly active, with 488 representative, Ki = 600 μM.(216a) This was not attributed to an effect on the pKa relative to the sulfate moiety; rather, the sulfate O atom was considered to be important for interacting with the enzyme. Fluorination of the benzylic carbon atom of 488 gave 489, which was 5-fold more potent and exhibited competitive inhibition kinetics in contrast to the mixed inhibition kinetic profile observed with 488. These potency observations were reproduced in the sulfonamide homologues 490 and 491, where α-fluorination enhanced inhibitory potency by 4-fold, although in this example both compounds exhibited mixed inhibitory kinetics.(216b) Interestingly, the potency of 491 increased with pH, with the Ki value = 28 μM at pH = 8.8 while that of the sulfonate 489 decreased, shifting 2-fold from 73 μM at pH = 7 to 147 μM at pH = 8.8, an observation attributed to the effect of ionization of the sulfonamide.
Difluoromethylsulfonates have also been probed as PTP1B phosphatase inhibitors where α-fluorination resulted in increased potency in two series, as illustrated by comparing data for the MMPs 492/493 and 494/495.(218) Perhaps not surprisingly for a monoionic species, 493 and 495 were less potent PTP1B phosphatase inhibitors than the phosphonate homologues 497 and 499, where α-fluorination also enhanced potency over the unsubstituted compound 496 and 498.(218)
Carbonic anhydrase is a Zn2+-dependent enzyme that exhibits affinity for primary sulfonamide moieties which coordinate to the metal.(219) Fluorination α- to the sulfonamide moiety led to a progressive increase in potency, with difluoro(phenyl)methanesulfonamide (502) 10-fold more potent than the prototype 500, while the monofluoro derivative 501 fell between these bookends (Table 40). The effect was more dramatic when comparing the activity of methylsulfonamide 503 with its CF3 congener 504, where the SARs reflected a close correlation between potency and pKa value that was consistent with the more potent inhibitors being those more ionized at neutral pH.(220)
Table 40. Carbonic Anhydrase Inhibitor Activity Associated with Sulfonamides 500504
  IC50 (nM)pKa
500PhCH2SO2NH263010.5
501PhCHFSO2NH22208.8
502PhCF2SO2NH2587.7
503CH3SO2NH265010.8
504CF3SO2NH2<26.3

CF2 as an Oxygen Bioisostere in Heterocycles

The morpholine heterocycle has long been a staple of drug design when a moderately basic ring system is required because the introduction of the oxygen atom into piperidine reduces the pKa by 2.6 units compared to piperidine (Table 41).(221) Other electron withdrawing elements that exert a similar effect but offer a range of lipophilicities include sulfur substitution, with thiomorpholine dioxide the most powerful of this series that reduces the pKa of piperidine by a more substantial 5.7 units.(222−224) Dual fluorination at the 4-position of piperidine modulates the pKa to the same extent as morpholine but offers ∼2.5 units of increased lipophilicity accompanied by a 70% reduction in PSA, providing a useful heterocycle when physicochemical properties are being optimized. As a consequence, 4,4-difluoropiperidine has been explored extensively by medicinal chemists; however, only a synopsis of the applications is presented in the following section which also highlights examples where biochemical emulation is poor.
Table 41. Experimentally Measured pKa Values for the Conjugate Acids of a Series of Heterocyclic Amines
The morpholine derivative 505 is a potent inhibitor of the class 3 tyrosine kinase macrophage colony-stimulating factor-1 receptor (FMS) but was poorly stable in HLM, with just 5.2% of the parent remaining after 10 min of incubation.(225) In contrast, the difluoropiperidine analogue 506 fully retained the enzyme inhibitory properties of 505 while offering enhanced metabolic stability in HLM, with 83% of the parent drug remaining intact after 10 min of incubation. A similar relative profile was seen when the compounds were incubated in RLM. In the selective cannabinoid CB2 agonist series represented by 507510, the parent piperidine 507 and 4,4-difluorinated homologue 509 offered potency superior to the more polar morpholine 508 and, particularly, the thiomorpholine dioxide 510, a reflection of the lipophilic nature of the receptor binding site.(226) However, while potency increased in parallel with lipophilicity in this series, rat clearance was higher for 507 and 509 compared to 508, while 510 was too weakly active to qualify for testing, indicating a need to carefully balance physicochemical properties.
The 4,4-difluoropiperidine moiety of 512 was an effective replacement for the morpholine heterocycle in 511 in a series of histamine-3 receptor inverse agonists, with both compounds exhibiting comparable affinity for the human receptor.(227) The prototype 511 was also a potent rat H3 receptor ligand that exhibited high selectivity over the hERG channel (21% inhibition at 10 μM) and CYP inhibition (IC50 > 30 μM) while presenting good metabolic stability in mouse, rat, dog, monkey, and human LMs (t1/2 > 40 min), high Caco-2 cell permeability, and low plasma protein binding. However, the in vivo clearance of 511 in the rat was very high and the molecule was extensively distributed to tissues, with a high volume of distribution, a large brain to plasma ratio, and an extended brain residence time. The fluorinated piperidine 512 exhibited acceptable metabolic stability in vitro but, unfortunately, exhibited a short 30 min t1/2 in vivo.
Careful modulation of the pKa of the SYK inhibitors 513515 was of importance to the PK profile of these molecules.(228) Although the potency of 515 was an order of magnitude better than the morpholine compound 514 while maintaining mild basicity relative to 513, in this series the morpholine heterocycle ultimately offered the optimal compromise of good oral bioavailability and efficacy in a rat Arthus model. However, 514 was genotoxic in an Ames mutagenicity assay, and 515 proved to be an inadequate substitute because its exposure in vivo was lower than for 514, attributed to higher clearance.
An interesting application of CF2/O isosterism is provided by the development of the melanin concentrating hormone receptor 1 (MCHR1) inhibitor 518, which was advanced into clinical trials as a phosphate prodrug of the alcohol for the treatment of obesity.(229) While the oxetane 516 showed high plasma exposure in rats following PO dosing, the compound was ineffective at inducing weight loss in a 4 day diet-induced obese (DIO) rat study, attributed to low brain and plasma concentrations at 20 h postdose. Reversion to the cyclobutane analogue 517 as a means of increasing lipophilicity provided an avenue forward but further modification to 518 was required in order to slow metabolism. This compound had adequate metabolic stability in rat LMs and when dosed as the glycine ester prodrug at a dose of 10 mg/kg, high plasma (4.5 μM) and brain (11.3 μM) levels were observed at the 8 h time point, reflecting a brain to plasma ratio of 2.5. Administration of a phosphate prodrug of 518 to DIO rats at a dose of 0.3 mg/kg resulted in a 5% weight loss, and this compound exhibited no evidence of the hepatobiliary lesions that had been seen with earlier compounds in the series when administered daily to rats at doses of up to 100 mg/kg for 30 days.(229)
A CF2 moiety appears to be an acceptable substitute for ether oxygen atom of the sodium–glucose cotransporter-2 (SGLT2) inhibitor dapaglifozin (519), with 520 claimed to exhibit a longer duration of glucosuria in vivo in rats.(230a) This work complements studies that successfully replaced the C-4 carbinol of 519 with a gem-fluoromethylene moiety.(231b)
However, there are a number of examples where a gem-difluoromethyl moiety has been found to be an inadequate substitute for a heterocyclic oxygen atom in a biochemical setting. For example, the 4,4-difluoropiperidine 522 derived from 521, an antagonist of the dopamine D4 receptor, exhibits several-fold lower binding affinity than the morpholine-based prototype.(231) In another example, the morpholine ring of the PI3K α, γ, and δ inhibitor 523 was uniquely active compared to the 4,4-difluoropiperidine analogue 524 and the thiomorpholine dioxide 525.(232)

ArCF2CH3 and ArOR Bioisosterism

The difluoroethyl moiety has been advocated as a bioisostere of an aromatic CH3O substituent based on the structural metaphor depicted in Figure 37, with recognition that the conformational preferences of the two substituents may be quite different, although the difluoroalkyl substituent may be conformationally flexible.(233,234) An example where a 1,1-difluoroethyl substituent offered advantage is found in the series of inhibitors of the kidney urea transporter UT-B represented by 526529 captured in Table 42.(235) While the OCH3 derivative 526 exhibited good potency, metabolic stability in rat liver microsomes was very poor and fluorination of the methyl group was not found to be a viable option to solve this problem because 527 suffered a 10-fold loss in potency, although metabolic stability improved dramatically. The ethyl derivative 528 restored potency but metabolic stability was also inadequate, a problem ultimately solved by introducing the 1,1-difluoroethyl substituent, with 529 offering an excellent compromise of targeted properties.

Figure 37

Figure 37. Proposed isosterism between anisole and (1,1-difluoroethyl)benzene.

Table 42. SARs and Metabolic Stability of 526529, Inhibitors of the Kidney Urea Transporter UT-B
 RIC50 (nM)% remaining in RLMs
526CH3O1046
527CF3O111095
528CH3CH211<5
529CH3CF21496
In the series of Takeda G-protein-coupled receptor 5 (TGR5) agonists 530534 compiled in Table 43, a CF2CH3 substituent offered increased metabolic stability in human liver microsomes when paired with the pyridine heterocycle, as configured in 534.(236) The OCH3 derivative 530 offered poor agonist potency, but this was improved by the introduction of substituents that lowered the constraint toward coplanarity, with OCF3 (531), CH2CH3 (532), and CF2CH3 (533) substantially more potent. However, metabolic stability in HLM was an issue for 530533, solved by the pyridine analogue 534, which has a lower E Log D value, although this was accompanied by some reduction of intrinsic agonist potency. Nevertheless, 531 was the compound selected for more advanced in vivo studies.(236)
Table 43. SARs and Metabolic Stability of TGR5 Agonists 530534
 RXinduced human TGR5 EC50 (nM)CLint human (μL/min/mg)
530OCH3CH13796
531OCF3CH2.3184
532CH2CH3CH9.2238
533CF2CH3CH2.7211
534CF2CH3N4318

Fluorinated Alkoxy Moieties and Mimesis

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Conformational Aspects of Fluorinated Alkoxy Moieties

A probe of the CSD confirmed previous literature observations that in the absence of dual ortho substitution, Ar-OCH3 prefers a coplanar arrangement of the aromatic ring and the O–CH3 bond favored by ∼3 kcal/mol (Figure 38).(237−239) This is a consequence of rehybridization of the oxygen atom to allow overlap with the unsaturated ring which overcomes allylic 1,3-strain. In contrast, Ar-OCF3 favors (by ∼0.5 kcal/mol) a conformation in which the O–CF3 bond is orthogonal to the plane of the aromatic ring, attributed to the reduced electronic overlap between the now electron deficient oxygen atom and the aromatic system that allows allylic 1,3-strain to dominate, furthered by the increased size of fluorine compared to hydrogen. In addition, a hyperconjugative interaction in which one of the lone pairs of electrons on the oxygen atom donates into one of the C–F σ* orbitals is believed to contribute to stabilizing the orthogonal topography. An assessment of the Ar-OCHF2 substituent revealed no strong preference for a specific conformation although the analysis was based on only 22 examples in the CSD. However, in two cases examined more closely, the C(Ar)–C(Ar)–O–C torsion angle was close to 90°, but the fluorine atoms adopted an endoexo arrangement in one example and an endoendo topography in the other. Thus, fluorination of the alkyl moiety of alkyl phenol ethers allows the aryl substituent to function conformationally as mimic of an alkyl substituent.

Figure 38

Figure 38. Conformational aspects of anisole, PhOCF3, and PhOCHF2.

Developability Aspects of Fluorinated Alkoxy Moieties

Fluorination of the alkyl moiety of phenol ethers has been explored broadly in drug design, and replacing the OCH3 of anisole derivatives with an OCF3 is a common tactic in drug design that is often focused on enhancing metabolic stability based on the premise of mitigating O-demethylation. However, this tactic is not always successful in increasing metabolic stability, dependent upon the potential for alternative sites of metabolism to become a dominant path. This phenomenon has been explored in some detail based on an analysis of MMPs examining the effect of substituting OCH3 by both OCF3 and the less common OCHF2 on metabolic stability, lipophilicity, membrane permeability, and conformation.(237a) The successive replacement of hydrogen by fluorine in anisole leads to a progressive but nonlinear increase in cLog P values, with increments of 0.17, 0.27, and 0.66 for a total of 1.1 log units, accompanied by an increase in MW of 54 for the OCF3 derivative. Measured Log D values confirmed the increased lipophilicity which ranged from 0.3 to 1.3 units for an OCF3 for OCH3 change while an OCHF2 reduced Log D by 0.3–0.7 log units compared to OCF3. However, the analysis of 439 MMPs where the only difference was a OCF3 for OCH3 substitution indicated that this change had no clear advantage with respect to improving metabolic stability in HLM. Moreover, the analysis revealed a significant difference in favor of OCH3 (70% of the MMPs) substitution toward improving passive membrane permeability. The comparison of OCHF2 with OCF3 was based on 149 MMPs and indicated that although there were compound-specific effects, there was a small overall advantage for OCHF2. In the membrane permeability assay, a OCHF2 for OCF3 substitution showed improved permeability in 67% of cases examined. This was attributed to the OCHF2 moiety being able to adopt an endoendo conformation that is similar in lipophilicity to OCF3, attributed to cancellation of bond polarities, while the endoexo state is more hydrophilic due to a 3-fold increase in polarity, which may explain the reduced Log D values. In a comparison between OCHF2 and OCH3, the former is more lipophilic by 0.2–0.6 log units, and in the HLM MMP analysis, the OCHF2 substituent showed an advantage over OCH3 that was statistically significant. However, in the membrane permeability comparison, the OCH3 derivatives were in general more permeable than their OCHF2 analogues when the parent molecule fell into the high or low permeability bin, while in the midrange bin, the two moieties were similarly permeable. The conclusion from this study was that OCHF2 offers advantage over both OCH3 and OCF3 during optimization as a means of balancing lipophilicity and molecular weight, conferring improved metabolic stability without compromising membrane permeability.(237a) Nevertheless, there are examples where fluorination of an anisole moiety has a positive effect on metabolic stability, illustrated by comparisons within the series of corticotropin releasing factor-1 (CRF-1) inhibitors 535538 compiled in Table 44.(240) In this series, replacing the OCH3 of 535, a site of metabolic lability, with either OCF3 (536) or OCHF2 (537), led to reduced intrinsic clearance in HLM although there was sensitivity to the absolute configuration at the cyclopropyl ethyl substituent with the (S)-isomer 538 metabolically less stable.
Table 44. Binding Potency and Metabolic Stability of a Series CRF-1 Inhibitors
 RCH3/CF3 configurationCRF-1 IC50 (nM)intrinsic clearance in HLM (mL/min/kg)
535CH3R1.1130
536CF3R6.530
537CHF2R0.4622
538CHF2S1.062

Fluorination of Alkyl Phenyl Ethers and Conformation

An example where influencing the conformation of an alkyl phenyl ether by fluorination may have played a role in modulating potency is provided by the cholesteryl ester transfer protein (CETP) inhibitors 539 and 540, where the latter is 8-fold more potent than the former.(241) In another example, the SAR associated with the HCV NS4B inhibitors 541544 suggested that an orthogonal projection of the C-6 substituent was important for HCV GT-1b replicon inhibition because the methoxy derivative 541 was 10-fold less potent than substituents that favor a noncoplanar topography.(164c)

Fluorine As a Nitrile Bioisostere

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The similarity of the biochemical profiles of 316 and 317 provide an example of a bioisosteric relationship between fluorine and the nitrile moiety.(145) Bioisosterism between these substituents has also been proposed in the context of the series of dual 5HT1A agonists and 5-HT reuptake inhibitors 545550.(242) An analysis of MEPs and dipole moments of 5-cyano- and 5-fluoro-substituted indoles confirmed the potential for a bioisosteric relationship, with the C–F more similar to a C–CN moiety than a C–Cl bond because the MEP maps and dipole vector for the 5-chloroindole were more similar to the parent. In the event, the fluoro and cyano MMPs 546/548 and 549/550 profiled similarly in the binding and reuptake assays, while the 5-chloro-substituted analogue 547 of 548 was markedly less potent and behaved more like the parent compound 545 in the reuptake inhibition assay.(242) The two benzodioxole analogues 549 and 550 showed similar efficacy in vivo in the ultrasonic vocalization test as a measure of in vivo 5-HT1A antagonism, and although subsequent studies focused on the nitrile series, the 5-fluoro analogues performed in a very similar fashion where comparisons were made. These studies culminated in the identification of viladozone (551), which was approved as an antidepressant by the FDA in 2011; however, the 5-fluoro analogue 552 presented an analogous profile in a range of assays, confirming the C–F/C–CN isosterism in this context.

The SF5 Moiety

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DSM-265 (246) is first SF5-containing drug to enter clinical trials and the in vitro comparison between 246 and 245 suggests a potential bioisosteric relationship between the SF5 and CF3 substituents (Table 25). Indeed, the SF5 moiety has been viewed as a “super CF3 group”; however, these two substituents are quite different in shape, size, lipophilicity, and electron withdrawing properties, as captured by the data summarized in Table 45.(243,244) The SF5 substituent is larger in volume than a CF3 but smaller than a tert-butyl moiety and possesses an octahedral geometry that presents a pyramidal electron density that is quite different from the tetrahedral shape of CF3, where the electron density is presented as an inverted cone (Figure 39).(243,245) The SF5 moiety is a more powerful electron withdrawing substituent than CF3 but similar to SO2CH3 and NO2 and may be considered to be a peripheral member of the family of “superacceptor” substituents that resemble sulfones in which fluorine has a prominent presence, with the key parameters also captured in Table 45.(246) The SF5 substituent is more lipophilic than either a CH3SO2 or a CF3SO2 substituent, thereby conferring good membrane permeability while being metabolically stable and chemically robust.

Figure 39

Figure 39. Comparison of the shapes of the CF3 and SF5 substituents.

Table 45. Comparison of the Electron Withdrawing (σp), Lipophilicity (π), and Substituent Dipole (μ) Values for the tert-Butyl, Nitro, SO2CH3, and a Series of Fluorinated Substituents(244)a
a

*A negative value indicates that the negative end of the dipole vector is toward the substituent.

Medicinal chemistry applications of the SF5 moiety have largely been limited by a lack of convenient synthetic access to suitable building blocks, but considerable progress has been made toward developing new methodology, and this substituent is beginning to be explored in a variety of settings, although still most typically as a homologue of the CF3 substituent.(4a,247) In the series of Trypanosoma cruzi trypanothione reductase inhibitors 553555, the CF3- and SF5-substituted compounds 553 and 554, respectively, offered comparable potency and a modest advantage over the tert-butyl derivative 555.(248) However, a kinetic analysis indicated that while 553 was a competitive inhibitor, both 554 and 555 exhibited a mixed competitive–uncompetitive kinetic profile. Compound 554 was docked into the active site of Trypanosoma cruzi trypanothione reductase with the orientation guided by X-ray cocrystal structures obtained with closely related structures, and the key interactions proposed are depicted in Figure 40. The comparable binding affinity of the bulkier inhibitor 554 compared to the smaller CF3 derivative 553 was attributed to the stronger electron withdrawing nature of the SF5 substituent that might potentially lead to an increase in the strength of the T-shaped interaction of the attached phenyl ring with the electron-rich Trp21, Tyr110, and Met113 residues of the enzyme.(248)

Figure 40

Figure 40. Proposed drug–target interactions between 554 and T. cruzi trypanothione reductase based on docking of the ligand into the active site of the enzyme.

In the matched pair of cannabinoids 556 and 557, the SF5 derivative 557 exhibited a modest 2-fold increased potency at CB1 receptors, while in the thymidine phosphorylase inhibitors 558 and 559, there is a 4-fold advantage for the SF5 substituent in 559 compared to the CF3 prototype 558.(249,250) The antidepressant drug fluoxetine (560) is a selective serotonin reuptake inhibitor that also demonstrates affinity for several serotonin receptors.(251) The SF5-substituted analogue 561 exhibited reduced binding to 5HT2a and 5HT2c receptors compared to 560 but had comparable affinity for 5HT2b receptors. In the case of fenfluramine (562), the SF5 analogue 563 exhibited 10-fold higher affinity for 5HT2b and 5HT6 receptors than the progenitor.(251)
The SF5 moiety continues to be of contemporary interest as a substituent in drug design with the Mtb inhibitor 565 profiling similarly to the CF3 analogue 564, although protein binding was higher for the former compound (99.7%) than the latter (99.1%).(252) The oxindole derivatives 566 and 567 have been profiled as kinase inhibitors that express cytotoxicity toward the T47D cancer cell line with EC50 values of 490 and 350 nM, respectively.(253) While modeling studies were utilized in the design of 566 and 567, examples of where the SF5 substituent confers a specific advantage based on its unique shape and electronic properties remain to be described.

Conclusion

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The unique properties of fluorine continue to reveal itself through the creative application of this unusual element in drug design, with recognition of its potential for mimicking a number of functionalities established as a prominent attribute of this interesting element. The small size of fluorine coupled with the high C–F bond strength has inspired its extensive application as a bioisosteric replacement for the hydrogen atom, particularly with respect to modulating the metabolism and conformation of a molecule. However, the electronic properties of a C–F bond have allowed it to effectively mimic carbonyl, hydroxyl, or nitrile functionality in circumstances that are often very much dependent on context. Thus, specific emulation of these functionalities is often based more on a bioisosteric rather than an isosteric relationship, which can add an element of unpredictability to their application in drug design. The powerful electron withdrawing properties of this electronegative element influence the basicity of proximal amines to an extent that can render an amide mimetic. Moreover, the partial fluorination of methyl groups can lead to polarization of a C–H bond that allows it to function as a H-bond donor that although weaker than more established donors has been shown to be of importance in drug–target interactions. The development of new synthetic methodologies continues to provide facile and effective access to new structural elements containing fluorine that, in turn, are contributing to a deeper understanding of the element and stimulating new applications that often have bioisosterism as an underlying basis. The many examples illustrated in this synopsis reflect the creativity of the medicinal chemistry community at large and anticipate the continued development and application of fluorine in drug design.

Author Information

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  • Corresponding Author
    • Notes
      The author declares the following competing financial interest(s): I am an employee and shareholder of Bristol-Myers Squibb.

    Biography

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    Nicholas A. Meanwell

    Nicholas A. Meanwell received his Ph.D. degree from the University of Sheffield and conducted postdoctoral studies at Wayne State University before joining Bristol-Myers Squibb in 1982. He has been associated with the discovery of BMY-433771, an inhibitor of respiratory syncytial virus fusion, the HIV-1 attachment inhibitor prodrug fostemsavir, the HIV-1 maturation inhibitor BMS-955176, and the marketed HCV inhibitors asunaprevir (NS3, Sunvepra), daclatasvir (NS5A, Daklinza), and beclabuvir (NS5B). He is the co-recipient of a 2014 PhRMA Research and Hope Award for Biopharmaceutical Industry Research and a 2017 ACS Heroes of Chemistry Award. He was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award and was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015.

    Acknowledgments

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    I thank Professors Günter Haufe (University Münster) and Frédéric Leroux (University of Strasbourg) for sowing the seeds of this manuscript. Drs. Dinesh Vyas, Kap-Sun Yeung, and Professor Günter Haufe and two reviewers are thanked for their critical review of an early version of the manuscript, while Dr. Makonen Belema is thanked for reviewing all versions of the article.

    Abbreviations Used
    AML

    acute myeloid leukemia

    BACE-1

    β-site amyloid precursor protein cleaving enzyme 1

    BCP

    [1.1.1]-bicyclopentane

    BTK

    Bruton’s tyrosine kinase

    Cdk

    cyclin-dependent kinase

    CETP

    cholesteryl ester transfer protein

    CFTR

    cystic fibrosis transmembrane regulator

    CGRP

    calcitonin gene-related peptide

    CRF-1

    corticotropin releasing factor-1

    CSD

    Cambridge Structural Database

    CYP

    cytochrome P enzyme

    DFT

    density functional theory

    DHODH

    dihydroorotate dehydrogenase

    DIO

    diet-induced obese

    DPP-4

    dipeptidyl peptidase-4

    ET

    endothelin

    FAAH

    fatty acid amide hydrolase

    FAP

    fibroblast activation protein

    FKBP

    FK506-binding protein

    FLT3

    FMS-like tyrosine kinase 3

    F-OPA

    fluorinated olefinic peptide nucleic acid

    FXa

    factor Xa

    GABA

    γ-aminobutyric acid

    GSH

    glutathione

    hAR

    human androgen receptor

    hBRS-3

    human bombesin receptor subtype-3

    HCV

    hepatitis C virus

    HIV-1

    human immunodeficiency virus-1

    HLM

    human liver microsomes

    hPTH

    human parathyroid hormone

    5-HT

    5-hydroxytryptamine (serotonin)

    Hyp

    4-(R)-hydroxy-l-proline

    IDH2

    isocitrate dehydrogenase 2

    IV

    intravenous

    LM

    liver microsomes

    MCHR1

    melanin concentrating hormone receptor 1

    MEK1

    MAP kinase kinase 1

    MEP

    molecular electrostatic potential

    MGAT

    acyl-CoA:monoacylglycerol acyltransferase

    MI

    metabolite intermediate

    MMP

    matched molecular pairs

    Mtb

    Mycobacterium tuberculosis

    MW

    molecular weight

    NMDA

    N-methyl-d-aspartate

    PAMPA

    parallel artificial membrane permeability assay

    PDB

    Protein Data Bank

    Pf

    Plasmodium falciparum

    P-gp

    P-glycoprotein

    PI3Kα

    phosphatidylinositol-3 kinase-α

    PNMT

    phenylethanolamine N-methyltransferase

    PPARγ

    peroxisome proliferator-activated receptor-γ

    PSA

    polar surface area

    QM

    quantum mechanics

    RLM

    rat liver microsomes

    SAR

    structure–activity relationship

    STS

    steroid sulfatase

    TGR5

    Takeda G-protein-coupled receptor 5

    WGA

    wheat germ agglutinin

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    • Abstract

      Figure 1

      Figure 1. Key drug–target interactions between 29 and the PI3Kα enzyme and conformational bias provided by an intramolecular O to S interaction.

      Figure 2

      Figure 2. Atropoisomerism associated with 4-(perfluoropropan-2-yl)-1H-indazol-5-amine.

      Scheme 1

      Scheme 1. Metabolism of 63 and the Release of 66

      Scheme 2

      Scheme 2. Metabolic Activation Pathway Deduced for the DPP-4 Inhibitor 67

      Scheme 3

      Scheme 3. Cytochrome P450-Mediated Metabolism of the 1,3-Benzodioxole Moiety to a MI Complex

      Figure 3

      Figure 3. Preferred conformation of 82 at the GABAA receptor (A) and the GABAC receptor and the transaminase enzyme (B) deduced from an evaluation of 83 and 84.

      Figure 4

      Figure 4. Proposed active conformation of NMDA at the GluN2A and GluN2B receptors after analysis of 91 and 92.

      Figure 5

      Figure 5. Conformational preferences of N-acetyl-proline methyl ester (94) (A), N-acetyl-4-(R)-fluoro-l-proline methyl ester (95) (B), and N-acetyl-4-(S)-fluoro-l-proline methyl ester (96) (C).

      Figure 6

      Figure 6. Acetamide conformation of 94 depicting an n → π* interaction.

      Figure 7

      Figure 7. Geometry of 1,1-difluoroalkanes (A), the 1,4-di-CF2 motif (B), and conformational preferences for 1,2-difluoro- (C) and 1,3-difluoro-alkanes (D).

      Scheme 4

      Scheme 4. Metabolism of 132

      Figure 8

      Figure 8. Core structures of MMPs of N-phenylamides and benzamides examined in a PAMPA.

      Figure 9

      Figure 9. Comparison of the dipole moments and vectors of difluorinated benzenes and azines.

      Figure 10

      Figure 10. Key interactions between CHK1 kinase and 190 in the cocrystal structure.

      Figure 11

      Figure 11. Structures and cathepsin L inhibitory data for 195204.

      Figure 12

      Figure 12. Proposed relationship between a piperazine lone pair of electrons and the fluorine atom of a 4-fluoropiperidine ring.

      Figure 13

      Figure 13. Key interactions between inhibitor 218 and thrombin.

      Figure 14

      Figure 14. Key drug–target interactions between the CF3 substituent of 224 and the p53 protein.

      Figure 15

      Figure 15. Key drug–target interactions between inhibitor 227 and BTK.

      Figure 16

      Figure 16. Calculated energies of the σ-hole and π-hole associated with perfluorotoluene.

      Figure 17

      Figure 17. Key interactions between 234 and IDH2 in the cocrystal stucture.(110b)

      Figure 18

      Figure 18. Key interactions between 235 and the NmrA-like family domain containing protein 1 NMRAL1 in the cocrystal complex.(111)

      Figure 19

      Figure 19. Proposed dipole interactions between 248 and Aurora A kinase leading to a conformational change in the DFG loop of the enzyme.

      Figure 20

      Figure 20. Dipole moments and vectors that illustrate isosterism between an amide moiety and fluorinated alkene derivatives that contrasts with simpler alkenes.

      Figure 21

      Figure 21. Key interactions between and FVIIa and the benzamidine-based inhibitor 304.

      Figure 22

      Figure 22. Key drug–target interactions between 309 and the HCV NS5B polymerase protein.

      Figure 23

      Figure 23. Key drug–target interactions between MEK1 and inhibitor 314.

      Figure 24

      Figure 24. Structural overlays of 82 with 318 and 319 illustrating C–F and C═O mimicry.

      Scheme 5

      Scheme 5. Metabolism of 331333 by Steroid 5α-Reductase

      Scheme 6

      Scheme 6. Reaction Process Catalyzed by α,β-Dihydroxyacid Dehydratase

      Figure 25

      Figure 25. Isosteric relationship between formaldehyde and 1,1-difluoroethylene.

      Scheme 7

      Scheme 7. TDP-l-rhamnose Synthase-Catalyzed Reduction of 342 to 343

      Scheme 8

      Scheme 8. Postulated Reaction Pathway of 341 with TDP-l-rhamnose Synthase

      Figure 26

      Figure 26. Incorporation of the CF3CH2NH motif in a polypeptide backbone in register (B) or in a partially retro-inverted configuration (C) that mimics the amide of a conventional polypeptide (A).

      Figure 27

      Figure 27. Functional aspects of the mimicry between an amide and a sulfonamide moiety and CF3CH2NH and CHF2CH2NH.

      Figure 28

      Figure 28. Bond angles and lengths that illustrate topological mimesis between a urea and a fluoroenamide.

      Figure 29

      Figure 29. Calculated conformational preferences for α-fluoromethyl and α,α-difluoromethyl secondary amides.

      Figure 30

      Figure 30. Conformational preferences of the α-fluorinated enantiomers of 413 designed to illuminate the bound conformation.

      Figure 31

      Figure 31. Topologies and bond lengths associated with α-fluoro-substituted amides 416418 and urea 419 in the solid state.

      Figure 32

      Figure 32. Preferred conformation of a 2′-α-fluoro-substituted ribose compared with a 2′-β-fluoro substituted isomer and a 2′-β, 2′-α-difluoro-substituted ribose ring.

      Figure 33

      Figure 33. Key H-bonding interactions between a 2′-methyl ribose moiety (436) and the 2′-fluoro-2′-methyl homologue that is the ribose hallmark of 434.

      Figure 34

      Figure 34. Intermolecular H-bond observed in the single-crystal X-ray structure of oxadiazole 449.

      Figure 35

      Figure 35. Illustration of the functional mimicry between RSH and RCF2H in P1 residues incorporated into 450 and 452.

      Figure 36

      Figure 36. Geometric parameters for the phosphate, phosphonate, and difluoromethylenephosphonate moieties.

      Figure 37

      Figure 37. Proposed isosterism between anisole and (1,1-difluoroethyl)benzene.

      Figure 38

      Figure 38. Conformational aspects of anisole, PhOCF3, and PhOCHF2.

      Figure 39

      Figure 39. Comparison of the shapes of the CF3 and SF5 substituents.

      Figure 40

      Figure 40. Proposed drug–target interactions between 554 and T. cruzi trypanothione reductase based on docking of the ligand into the active site of the enzyme.

    • References

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